Quinazoline Compounds as Sodium Channel Blockers

ABSTRACT

The invention relates to aryl substituted quinazolines of Formula I, and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein G, A, and R 1 -R 4  are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel aryl and heteroaryl substituted quinazolyl compoundsand the use of these compounds as blockers of sodium (Na⁺) channels.

2. Background Art

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7: 144-158 (2008) and Kyle andIlyin, J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently 9 known members ofthe family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, H1) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family TTX Gene Tissue IC₅₀Disease Type Symbol Distribution (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurode- generation Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurode- generation Na_(v)1.3 SCN3A CNS15 — Pain Na_(v)1.4 SCN4A Skeletal 25 Myotonia Myotonia muscle Na_(v)1.5SCN5A Heart 2,000 Arrhythmia Arrhythmia muscle Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Eryther- Pain malgiaNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 may play a keyrole in various pain states, including acute, inflammatory and/orneuropathic pain. Deletion of the SCN9A gene in nociceptive neurons ofmice led to an increase in mechanical and thermal pain thresholds andreduction or abolition of inflammatory pain responses (Nassar et al.,Proc Natl. Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenyloin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents may beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin, J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebelleratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenyloin are occasionally used to treat neuropathic pain, such as fromtrigeminal neuralgia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)).Furthermore, based on a number of similarities between chronic pain andtinnitus, (Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res.28:271-275 (1987)) it has been proposed that tinnitus should be viewedas a form of chronic pain sensation (Simpson, et al., Tip. 20:12-18(1999)). Indeed, lidocaine and carbamazepine have been shown to beefficacious in treating tinnitus (Majumdar, B. et al., Clin.Otolaryngol. 8:175-180 (1983); Donaldson, Laryngol. Otol. 95:947-951(1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of quinazolyl compoundsrepresented by Formula I, below, and the pharmaceutically acceptablesalts, prodrugs and solvates thereof (collectively referred to herein as“Compounds of the Invention”), as blockers of sodium (Na⁺) channels.

The present invention is also related to treating a disorder responsiveto the modulation, in particular blockade of sodium channels in a mammalsuffering from excess activity of said channels by administering aneffective amount of a Compound of the Invention as described herein.

Compounds useful in the present invention have not been heretoforereported. Thus, one aspect of the present invention is directed to novelcompounds of Formula I, as well as their pharmaceutically acceptablesalts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of Formula I, and their pharmaceutically acceptablesalts, prodrugs and solvates, as modulators, in particular blockers ofsodium channels.

A further aspect of the present invention is to provide a method fortreating pain (e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain, postoperative pain and inflammatory pain,or surgical pain) by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment. Specifically, thepresent invention provides a method for preemptive or palliativetreatment of pain by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment.

A further aspect of the present invention is to provide a method fortreating stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,migraine, familial primary erythromelalgia, paroxysmal extreme paindisorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, by administering an effectiveamount of a Compound of the Invention to a mammal in need of suchtreatment.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating a disorder responsive to the blockade ofsodium ion channels, said pharmaceutical composition containing aneffective amount of a Compound of the Invention in a mixture with one ormore pharmaceutically acceptable carriers.

Also, an aspect of the present invention is to provide a method ofmodulating, preferably blocking, sodium channels in a mammal, whereinsaid method comprises administering to the mammal an effective amount ofat least one Compound of the Invention.

A further aspect of the present invention is to provide a Compound ofthe Invention for use in treating pain (e.g., acute pain, chronic pain,which includes but is not limited to, neuropathic pain, postoperativepain and inflammatory pain, or surgical pain) in a mammal.

A further aspect of the present invention is to provide a Compound ofthe Invention for use in the treatment of stroke, neuronal damageresulting from head trauma, epilepsy, seizures, general epilepsy withfebrile seizures, severe myoclonic epilepsy in infancy, neuronal lossfollowing global and focal ischemia, migraine, familial primaryerythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy,ataxia, dystonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia in a mammal.

A further aspect of the present invention is to provide radiolabeledCompounds of the Invention and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the present invention further provides a method forscreening a candidate compound for its ability to bind to a sodiumchannel or a sodium channel subunit using a radiolabeled Compound of theInvention. In certain embodiments, the compound is radiolabeled with ³H,¹¹C, or ¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the mixturewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

A further aspect of the present invention is to provide the use of aCompound of the Invention in the manufacture of a medicament fortreating pain in a mammal.

In one embodiment, the invention provides the use of a Compound of theinvention in the manufacture of a medicament for palliative orpreemptive treatment of pain, such as acute pain, chronic pain, orsurgical pain.

A further aspect of the present invention is to provide the use of aCompound of the Invention in the manufacture of a medicament fortreating stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,migraine, familial primary erythromelalgia, paroxysmal extreme paindisorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia in a mammal.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Na channels. In view of this property,compounds of Formula I, and the pharmaceutically acceptable salts,prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of sodium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof, wherein:

R¹, R², R³, and R⁴ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy,hydroxyalkyl, haloalkyl, cyano; amino, alkylamino, dialkylamino, alkoxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylcarbonylamino, alkylcarbonyloxy, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonylamino, (alkylsulfonylamino)alkyl, ureido,(aminocarbonyl)alkylamino, and (carboxyalkyl)amino;

G is G¹, G², G³, or G⁴, wherein

G¹ is —NR⁵R⁶, wherein

R⁵ is H, alkyl, or NH₂,

R⁶ is

a) H,

b) alkyl,

c) hydroxyalkyl,

d) (aminocarbonyl)alkyl,

e) (aminocarbonyl)(hydroxy)alkyl;

f) aminoalkyl,

g) alkylaminoalkyl,

h) dialkylaminoalkyl,

i) cycloalkyl, unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano;

j) (cycloalkyl)alkyl, wherein the cycloalkyl is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

k) aryl, unsubstituted or substituted with one or more substituents eachindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano;

l) arylalkyl, wherein the aryl group is unsubstituted or substitutedwith one or more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

m) heteroaryl, unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano;

n) heteroarylalkyl, wherein the heteroaryl group is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

o) heterocyclo, unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano; or

p) heterocycloalkyl, wherein the heterocyclo is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano; or

R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclic ring having carbon atoms and 1 or 2nitrogen atoms, wherein the heterocyclic ring is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of oxo, alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

G² is

p is 0, 1 or 2;

R⁷ is

a) —(CH₂)_(q)OH, wherein q is 0-5; or

b) selected from the group consisting of hydrogen, amino, alkylamino,dialkylamino, and alkoxy; and

R⁸ is hydrogen or a bond (i.e. —OR⁸ is ═O);

G³ is a 5- or 6-membered heteroaryl containing at least one nitrogenatom, wherein the heteroaryl is unsubstituted or substituted with one ormore substituents each independently selected from the group consistingof alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano; and

G⁴ is —OR⁹, wherein R⁹ is alkyl, alkenyl, alkynyl, hydroxyalkyl,aminoalkyl, alkylamino alkyl, dialkylaminoalkyl, aminocarbonylalkyl,carboxyalkyl, alkoxycarbonylalkyl, arylalkyl, heteroarylalkyl, aryl orheteroaryl, wherein said aryl and heteroaryl groups are unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

A is

wherein

A¹ is aryl or heteroaryl, any of which is optionally substituted;

X is —O—, —SO—, —SO₂—, —CH₂—, or —NH—; and

R¹³ and R¹⁴ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl.

In one embodiment, Compounds of the Invention are compounds of FormulaI, and the pharmaceutically acceptable salts, prodrugs and solventsthereof, as defined above, with the proviso that when G is G¹, where R⁵is hydrogen or alkyl and R⁶ is hydrogen, alkyl or cycloalkyl, and X isO, then no two of R¹, R², R³ and R⁴ are alkoxy at the same time.

In one embodiment, Compounds of the Invention are compounds of FormulaI, where G is G¹, that is —NR⁵R⁶, wherein R⁵ and R⁶ are as defined abovefor Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁵ in G¹ is H and R⁶ is as definedabove for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁵ in G¹ is alkyl and R⁶ is asdefined above for Formula I. Useful alkyl groups for R⁵ include straightchain and branched chain C₁₋₆ alkyl groups. Preferably, R⁵ is C₁₋₄alkyl. Useful alkyl groups for R⁵ include methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, and sec-butyl, and typically methyl andethyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁵ in G¹ is NH₂ and R⁶ is asdefined above for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is hydrogen and R⁵ is asdefined above for Formula I. In another embodiment, Compounds of theInvention are compounds of Formula I, wherein G¹ is —NH₂ or —NH(NH₂).

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is alkyl and R⁵ is asdefined above for Formula I. Useful alkyl groups for R⁶ include straightchain and branched chain C₁₋₆ alkyl groups. Preferably, R⁶ is C₁₋₄alkyl. Useful alkyl groups for R⁶ include methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, and sec-butyl, and typically methyl andethyl. In another embodiment, Compounds of the Invention are compoundsof Formula I, wherein G¹ is —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl),or —N(NH₂)(C₁₋₄ alkyl).

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is hydroxyalkyl and R⁵ isas defined above for Formula I. Useful hydroxyalkyl groups for R⁶include straight chain or branched chain mono-, di-, andtri-hydroxyalkyl groups, and typically straight chain or branched chainmono- and dihydroxyalkyl groups. Useful monohydroxyalkyl groups includemonohydroxy(C₂₋₆)alkyl groups, and preferably monohydroxy(C₂₋₄)alkylgroups, such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylethyl,and 2-hydroxy-1-methylpropyl. Useful dihydroxyalkyl groups includedihydroxy(C₂₋₆)alkyl groups, and preferably dihydroxy(C₂₋₄)alkyl groups,such as 1,2-dihydroxyethyl, 2,3-dihydroxypropyl,2-hydroxy-1-hydroxymethylethyl, and 1,3-dihydroxyprop-2-yl. In oneembodiment, R⁶ is any hydroxyalkyl as defined above and R⁵ is H. Inanother embodiment, R⁶ is any hydroxyalkyl as defined above and R⁵ isNH₂. In another embodiment, R⁶ is any hydroxyalkyl as defined above andR⁵ is C₁₋₄ alkyl. In another embodiment, Compounds of the Invention arecompounds of Formula I, where G is G¹, R⁵ is H, NH₂ or C₁₋₄ alkyl, andR⁶ is selected from the group consisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G¹ is selected from the group consisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is (aminocarbonyl)alkyland R⁵ is as defined above. Useful (aminocarbonyl)alkyl groups for R⁶include straight chain or branched chain mono- or di(aminocarbonyl)alkylgroups. Useful mono(aminocarbonyl)alkyl groups includemono(aminocarbonyl)C₁₋₆ alkyl groups, and preferablymono(aminocarbonyl)C₁₋₄ alkyl groups, such as (aminocarbonyl)methyl,1-(aminocarbonyl)ethyl, 2-(aminocarbonyl)ethyl, 1-(aminocarbonyl)propyl,2-(aminocarbonyl)propyl, 3-(aminocarbonyl)propyl,1-(aminocarbonyl)butyl, 2-(aminocarbonyl)butyl, 3-(aminocarbonyl)butyl,4-(aminocarbonyl)butyl, 1-(aminocarbonyl)-2-methylpropyl,2-aminocarbonyl-1-methylethyl, and 2-aminocarbonyl-1-methylpropyl.Useful di(aminocarbonyl)alkyl groups include di(aminocarbonyl)(C₂₋₆)alkyl groups, and preferably di(aminocarbonyl)(C₂₋₄)alkyl groups, suchas 1,2-di(aminocarbonyl)ethyl, 2,3-di(aminocarbonyl)propyl,2-(aminocarbonyl)-1-(aminocarbonyl)methylethyl, and 1,3-di(aminocarbonyl)prop-2-yl. In one embodiment, R⁶ is any (aminocarbonyl)alkylgroup as defined above and R⁵ is H. In another embodiment, R⁶ is any(aminocarbonyl)alkyl group as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any (aminocarbonyl)alkyl group as defined above and R⁵is C₁₋₄ alkyl. In another embodiment, Compounds of the Invention arecompounds of Formula I, where G¹ is selected from the group consistingof

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is(aminocarbonyl)(hydroxy)alkyl and R⁵ is as defined above. Useful(aminocarbonyl)(hydroxy)alkyl groups for R⁶ include straight chain orbranched chain (aminocarbonyl)(hydroxy)alkyl groups. Useful(aminocarbonyl)(hydroxy)alkyl groups include(aminocarbonyl)(hydroxy)C₂₋₆ alkyl groups, and preferably(aminocarbonyl)(hydroxy)C₂₋₄ alkyl groups, such as1-(aminocarbonyl)-2-hydroxyethyl, 2-(aminocarbonyl)-2-hydroxyethyl,1-(aminocarbonyl)-2-hydroxypropyl, 1-(aminocarbonyl)-3-hydroxypropyl,2-(aminocarbonyl)-3-hydroxypropyl, 2-hydroxy-3-(aminocarbonyl)propyl,1-(aminocarbonyl)-2-hydroxybutyl, 1-(amino carbonyl)-3-hydroxybutyl,1-(aminocarbonyl)-4-hydroxybutyl, 2-(aminocarbonyl)-3-hydroxybutyl,2-(aminocarbonyl)-4-hydroxybutyl, 2-hydroxy-3-(aminocarbonyl)butyl,2-hydroxy-4-(aminocarbonyl)butyl, 3-hydroxy-4-(aminocarbonyl)butyl,1-(aminocarbonyl)-2-(hydroxymethyl)propyl,2-aminocarbonyl-1-(hydroxymethyl)ethyl, and2-aminocarbonyl-1-(hydroxymethyl)propyl. In one embodiment, R⁶ is any(aminocarbonyl)(hydroxy)alkyl group as defined above and R⁵ is H. Inanother embodiment, R⁶ is any (aminocarbonyl)(hydroxy)alkyl group asdefined above and R⁵ is NH₂. In another embodiment, R⁶ is any(aminocarbonyl)(hydroxy)alkyl group as defined above and R⁵ is C₁₋₄alkyl. In another embodiment, Compounds of the Invention are compoundsof Formula I, where G¹ is

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is aminoalkyl and R⁵ isas defined above. Useful aminoalkyl groups for R⁶ include straight chainand branched chain aminoalkyl groups. Useful aminoalkyl groups includeamino(C₁₋₆)alkyl groups, and preferably amino(C₁₋₄alkyl groups, such asaminomethyl, 2-aminoethyl, 1-aminoethyl, 1-aminopropyl, 2-aminopropyl,3-aminopropyl, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl,2-amino-1-methylethyl, and 2-amino-1-methylpropyl. In one embodiment, R⁶is any aminoalkyl as defined above and R⁵ is H. In another embodiment,R⁶ is any aminoalkyl as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any aminoalkyl as defined above and R⁵ is C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is alkylaminoalkyl and R⁵is as defined above. Useful alkylaminoalkyl groups for R⁶ includestraight chain and branched chain alkylaminoalkyl groups. Usefulalkylaminoalkyl groups include C₁₋₄ alkylamino(C₁₋₆)alkyl groups, andpreferably C₁₋₂ alkylamino(C₁₋₄)alkyl groups, such as methylaminomethyl,2-methylaminoethyl, 1-methylaminopropyl, 2-methylaminopropyl,3-methylaminopropyl, 1-methylaminobutyl, 2-methylaminobutyl,3-methylaminobutyl, 4-methylaminobutyl, 2-methylamino-1-methylethyl, and2-methylamino-1-methylpropyl. In one embodiment, R⁶ is anyalkylaminoalkyl as defined above and R⁵ is H. In another embodiment, R⁶is any alkylaminoalkyl as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any alkylaminoalkyl as defined above and R⁵ is C₁₋₄alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is dialkylaminoalkyl andR⁵ is as defined above. Useful dialkylaminoalkyl groups for R⁶ includestraight chain and branched chain dialkylaminoalkyl groups. Usefuldialkylaminoalkyl groups include di(C₁₋₄ alkyl)amino(C₁₋₆)alkyl groups,and preferably di(C₁₋₂ alkyl)amino(C₁₋₄alkyl groups, such asdimethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl,1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl,1-dimethylaminobutyl, 2-dimethylaminobutyl, 3-dimethylaminobutyl,4-dimethylaminobutyl, 2-dimethylamino-1-methylethyl, and2-dimethylamino-1-methylpropyl. In one embodiment, R⁶ is anydialkylaminoalkyl as defined above and R⁵ is H. In another embodiment,R⁶ is dimethylamino(C₂₋₄)alkyl and R⁵ is H. In another embodiment, R⁶ isany dialkylaminoalkyl as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any dialkylaminoalkyl as defined above and R⁵ is C₁₋₄alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is cycloalkyl,unsubstituted or substituted with one or more substituents, typically 1,2 or 3 substituents, each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. In one embodiment, R⁶is unsubstituted C₃₋₆ cycloalkyl. In another embodiment, R⁶ is C₃₋₆cycloalkyl substituted with one or more, preferably 1 or 2, substituentseach independently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano. Useful substituents for the cycloalkyl groupinclude C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl,halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₄ alkylamino(C₁₋₆)alkyl, di(C₁₋₄)alkylamino(C₁₋₆)alkyl,aminocarbonyl, carboxy, C₁₋₆ alkoxycarbonyl, and cyano; and preferablyC₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, halo(C_(IA))alkyl, halo(C_(IA))alkoxy,hydroxy, hydroxy(C₁₋₄)alkyl, amino, amino(C₁₋₄)alkyl, C₁₋₂alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C_(IA))alkyl, aminocarbonyl,carboxy, C₁₋₄ alkoxycarbonyl, and cyano. Useful C₃₋₆ cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which canbe unsubstituted or substituted as defined above. In one embodiment, R⁶is any cycloalkyl as defined above and R⁵ is H. In another embodiment,R⁶ is any cycloalkyl as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any cycloalkyl as defined above and R⁵ is C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is (cycloalkyl)alkyl,wherein the cycloalkyl group is unsubstituted or substituted with one ormore substituents, typically 1, 2 or 3 substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. Inone embodiment, R⁶ is unsubstituted (C₃₋₆ cycloalkyl)alkyl, andpreferably unsubstituted (C₃₋₆ cycloalkyl)(C₁₋₆)alkyl. In anotherembodiment, R⁶ is (C₃₋₆ cycloalkyl)alkyl, and preferably (C₃₋₆cycloalkyl)(C₁₋₆)alkyl, wherein the C₃₋₆ cycloalkyl is substituted withone or more, preferably 1 or 2, substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the cycloalkyl group include C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋6)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁ ₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl,amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful (C₃₋₆ cycloalkyl)(C₁₋₆)alkyl groupsinclude cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl,cyclobutylmethyl, cyclobutyl ethyl, cyclobutylpropyl, cyclopentylmethyl,cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyland cyclohexylpropyl, wherein the cycloalkyl group can be unsubstitutedor substituted as defined above. In one embodiment, R⁶ is any(cycloalkyl)alkyl as defined above and R⁵ is H. In another embodiment,R⁶ is any (cycloalkyl)alkyl as defined above and R⁵ is NH₂. In anotherembodiment, R⁶ is any (cycloalkyl)alkyl as defined above and R⁵ is C₁₋₄alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is aryl, unsubstituted orsubstituted with one or more substituents, typically 1, 2 or 3substituents, each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano. In one embodiment, R⁶ isunsubstituted C₆₋₁₄ aryl, and preferably C₆₋₁₂ aryl. In anotherembodiment, R⁶ is C₆ ₋₁₄ aryl, and preferably C₆₋₁₂ aryl, substitutedwith one or more, preferably 1 or 2, substituents each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the aryl group include C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl,amino, amino(C₁-6)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl,amino, amino(C₁₋₄alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful C₆₋₁₂ aryl groups include phenyl,naphthyl and biphenyl, which can be unsubstituted or substituted asdefined above. In one embodiment, R⁶ is any aryl as defined above and R⁵is H. In another embodiment, R⁶ is any aryl as defined above and R⁵ isNH₂. In another embodiment, R⁶ is any aryl as defined above and R⁵ isC₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is arylalkyl, wherein thearyl group is unsubstituted or substituted with one or moresubstituents, typically 1, 2 or 3 substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. Inone embodiment, R⁶ is unsubstituted C₆₋₁₄ aryl(C₁₋₆)alkyl, andpreferably C₆₋₁₂ aryl(C₁₋₄)alkyl. In another embodiment, R⁶ is C₆₋₁₄aryl(C₁₋₆)alkyl, and preferably C₆₋₁₂ aryl(C₁₋₄)alkyl, substituted withone or more, preferably 1 or 2, substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the aryl group include C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl,amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl,amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful C₆₋₁₂ aryl(C₁₋₄)alkyl groups includephenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, biphenylmethyl,2-biphenylethyl, wherein the aryl group can be unsubstituted orsubstituted as defined above. In one embodiment, R⁶ is any arylalkyl asdefined above and R⁵ is H. In another embodiment, R⁶ is any arylalkyl asdefined above and R⁵ is NH₂. In another embodiment, R⁶ is any arylalkylas defined above and R⁵ is C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is heteroaryl,unsubstituted or substituted with one or more substituents, typically 1,2 or 3 substituents, each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. In one embodiment, R⁶is unsubstituted heteroaryl, and preferably unsubstituted 5- or6-membered heteroaryl. In another embodiment, R⁶ is heteroaryl, andpreferably 5- or 6-membered heteroaryl, substituted with one or more,preferably 1 or 2, substituents each independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the heteroaryl group include C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl,amino, amino(C₁₋₄alkyl, C₁₋₂ alkylamino(C₁₋₄alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful 5- or 6-membered heteroaryl groupsinclude 5- or 6-membered heteroaryl groups having at least one nitrogenatom, such as pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl),imidazolyl (e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,2H-imidazol-2-yl, and 2H-imidazol-4-yl), 1,2,3-triazolyl (e.g.,1H-1,2,3-triazol-2-yl, 1H-1,2,3-triazol-4-yl, and1H-1,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g., 1H-1,2,4-triazol-3-yl and1H-1,2,4-triazol-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, andthiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl), isooxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, andpyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl),and pyrazinyl (e.g., pyrazin-2-yl and pyrazin-3-yl), which can beunsubstituted or substituted as defined above. In one embodiment, R⁶ isany heteroaryl as defined above and R⁵ is H. In another embodiment, R⁶is any heteroaryl as defined above and R⁵ is NH₂. In another embodiment,R⁶ is any heteroaryl as defined above and R⁵ is C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is heteroarylalkyl,wherein the heteroaryl group is unsubstituted or substituted with one ormore substituents, typically 1, 2 or 3 substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. Inone embodiment, R⁶ is unsubstituted heteroaryl(C₁₋₆)alkyl, andpreferably unsubstituted 5- or 6-membered heteroaryl(C₁₋₄alkyl. Inanother embodiment, R⁶ is heteroaryl(C₁₋₆)alkyl, and preferably 5- or6-membered heteroaryl(C₁₋₄)alkyl, substituted with one or more,preferably 1 or 2, substituents each independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the heteroaryl group include C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl,amino, amino(C₁₋₄alkyl, C₁₋₂ alkylamino(C₁₋₄alkyl,di(C₁₋₂)alkylamino(C₁₋₄alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful 5- or 6-membered heteroaryl groups inthe heteroarylalkyl group include 5- or 6-membered heteroaryl groupshaving at least one nitrogen atom, such as pyrrolyl (e.g., pyrrol-1-yl,1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., imidazol-1-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-imidazol-2-yland 2H-imidazol-4-yl), 1,2,3-triazolyl (e.g., 1,2,3-triazol-1-yl,1H-1,2,3-triazol-2-yl, 1H-1,2,3-triazol-4-yl, and1H-1,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g., 1,2,4-triazol-1-yl,1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isooxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), pyrazolyl (e.g.,pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl),pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl),pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl),pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl), and pyrazinyl(e.g., pyrazin-2-yl and pyrazin-3-yl), which can be unsubstituted orsubstituted as defined above. Typical heteroarylalkyl groups for R⁶include, for example, imidazol-1-ylmethyl, 2-(imidazol-1-yl)ethyl,3-(imidazol-1-yl)propyl, 4-(imidazol-1-yl)butyl, 1H-imidazol-2-ylmethyl,2-(1H-imidazol-2-yl)ethyl, 3-(1H-imidazol-2-yl)propyl,4-(1H-imidazol-2-yl)butyl, 2H-imidazol-4-ylmethyl,2-(2H-imidazol-4-yl)ethyl, 3-(2H-imidazol-4-yl)propyl,4-(2H-imidazol-4-yl)butyl, pyrrol-1-ylmethyl, 2-(pyrrol-1-yl)ethyl,3-(pyrrol-1-yl)propyl, 4-(pyrrol-1-yl)butyl, 1,2,3-triazol-1-ylmethyl,2-(1,2,3-triazol-1-yl)ethyl, 3-(1,2,3-triazol-1-yl)propyl,4-(1,2,3-triazol-1-yl)butyl, 1,2,4-triazol-1-ylmethyl,2-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,4-triazol-1-yl)propyl,4-(1,2,4-triazol-1-yl)butyl, pyridin-2-ylmethyl, 2-(pyridin-2-yl)ethyl,3-(pyridin-2-yl)propyl, and 4-(pyridin-2-yl)butyl. In one embodiment, R⁶is any heteroarylalkyl as defined above and R⁵ is H. In anotherembodiment, R⁶ is any heteroarylalkyl as defined above and R⁵ is NH₂. Inanother embodiment, R⁶ is any heteroarylalkyl as defined above and R⁵ isC₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is heterocyclo,unsubstituted or substituted with one or more substituents, typically 1,2 or 3 substituents, each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. In one embodiment,the heterocyclo is a 3-7 membered monocyclic ring system. In anotherembodiment, the heterocyclo is a 7-10 membered bicyclic ring system. Inone embodiment, R⁶ is unsubstituted 3-7 membered heterocyclo, andpreferably unsubstituted 5- or 6-membered heterocyclo. In oneembodiment, R⁶ is unsubstituted 7-10 membered heterocyclo. In anotherembodiment, R⁶ is a 3-7 membered heterocyclo, and preferably 5- or6-membered heterocyclo, substituted with one or more, preferably 1 or 2,substituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano. In another embodiment, R⁶ is a 7-10membered heterocyclo substituted with one or more, preferably 1 or 2,substituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano. Useful substituents for theheterocyclo group include C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl,amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. Useful 5- or 6-membered heterocyclo groupsinclude 5- or 6-membered heterocyclo groups having at least one nitrogenatom, such as pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), imidazolidinyl (e.g., imidazolidin-1-yl,imidazolidin-2-yl and imidazolidin-4-yl), 2-oxo-imidazolidinyl (e.g.,2-oxo-imidazolidin-1-yl and 2-oxo-imidazolidin-4-yl), oxazolidinyl(e.g., oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, andoxazolidin-5-yl), isooxazolidinyl (e.g., isoxazolidin-2-yl,isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl),3-oxo-isoxazolidinyl (e.g., 3-oxo-isoxazolidin-2-yl and3-oxo-isoxazolidin-4-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl,pyrazolidin-3-yl and pyrazolidin-4-yl), piperidinyl (e.g.,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl),2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl, 2-oxo-piperidin-3-yl,2-oxo-piperidin-5-yl and 2-oxo-piperidin-6-yl) and hexahydropyrimidinyl(e.g., hexahydropyrimidin-1-yl, hexahydropyrimidin-2-yl,hexahydropyrimidin-4-yl, and hexahydropyrimidin-5-yl), piperazinyl(e.g., piperazin-1-yl, piperazin-3-yl, and piperazin-4-yl), andmorpholinyl (e.g., morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl),which can be unsubstituted or substituted as defined above. Useful 7-10membered heterocyclo groups for R⁶ include9-azabicyclo[3.3.1]nonan-3-yl, which can be unsubstituted or substitutedas defined above. Further useful 7-10 membered heterocyclo groups for R⁶include endo-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl and8-methyl-8-azabicyclo[3.2.1]octan-3-yl. In one embodiment, R⁶ is anyheterocyclo as defined above and R⁵ is H. In another embodiment, R⁶ isany heterocyclo as defined above and R⁵ is NH₂. In another embodiment,R⁶ is any heterocyclo as defined above and R⁵ is C₁₋₄ alkyl. In anotherembodiment, R⁶ is 3-oxo-isoxazolidin-4-yl and R⁵ is as defined forFormula I. In another embodiment, R⁶ isendo-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl and R⁵ is as defined forFormula I. In another embodiment, Compounds of the Invention arecompounds of Formula I, wherein G¹ is selected from the group consistingof

wherein R¹⁷ is hydrogen or C₁₋₄ alkyl, and typically methyl or ethyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ is heterocycloalkyl,wherein the heterocyclo is unsubstituted or substituted with one or moresubstituents, typically 1, 2 or 3 substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano. Inone embodiment, the heterocyclo group in the heterocycloalkyl is a 3-7membered monocyclic ring system. In another embodiment, the heterocyclogroup in the heterocycloalkyl is a 7-10 membered bicyclic ring system.In one embodiment, R⁶ is heterocycloalkyl, wherein the heterocyclo groupis an unsubstituted 3-7 membered heterocyclo, and preferablyunsubstituted 5- or 6-membered heterocyclo. In one embodiment, R⁶ isheterocycloalkyl, wherein the heterocyclo group is an unsubstituted 7-10membered heterocyclo. In one embodiment, R⁶ is unsubstitutedheterocyclo(C₁₋₆)alkyl, and preferably unsubstituted 5- or 6-memberedheterocyclo(C₁₋₄alkyl. In another embodiment, R⁶ isheterocyclo(C₁₋₆)alkyl, and preferably 5- or 6-memberedheterocyclo(C₁₋₄)alkyl, wherein the heterocyclo is substituted with oneor more, preferably 1 or 2, substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents for the heterocyclo of the heterocycloalkyl groupinclude C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl,halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₄ alkylamino(C₁₋₆)alkyl, di(C₁₋₄)alkylamino(C₁₋₆)alkyl,aminocarbonyl, carboxy, C₁₋₆ alkoxycarbonyl, and cyano; and preferablyC₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy,hydroxy, hydroxy(C₁₋₄alkyl, amino, amino(C₁₋₄alkyl, C₁₋₂alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl,carboxy, C₁₋₄ alkoxycarbonyl, and cyano. Useful 5- or 6-memberedheterocyclo groups in the heterocycloalkyl include 5- or 6-memberedheterocyclo groups having at least one nitrogen atom, such aspyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), imidazolidinyl (e.g., imidazolin-1-yl,imidazolidin-2-yl and imidazolidin-4-yl), 2-oxo-imidazolidinyl (e.g.,2-oxo-imidazolidin-1-yl and 2-oxo-imidazolidin-4-yl), oxazolidinyl(e.g., oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, andoxazolidin-5-yl), isooxazolidinyl (e.g., isoxazolidin-2-yl,isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl),3-oxo-isoxazolidinyl (e.g., 3-oxo-isoxazolidin-4-yl and3-oxo-isoxazolidin2-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl,pyrazolidin-3-yl and pyrazolidin-4-yl), piperidinyl (e.g.,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl),2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl, 2-oxo-piperidin-3-yl,2-oxo-piperidin-5-yl and 2-oxo-piperidin-6-yl) and hexahydropyrimidinyl(e.g., hexahydropyrimidin-1-yl, hexahydropyrimidin-2-yl,hexahydropyrimidin-4-yl, and hexahydropyrimidin-5-yl), piperazinyl(e.g., piperazin-1-yl, piperazin-2-yl or piperazin-3-yl), andmorpholinyl (e.g., morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl),which can be unsubstituted or substituted as defined above. In anotherembodiment, R⁶ is heterocyclo(C₁₋₆)alkyl, wherein the heterocyclo is abicyclic 7-10 membered ring. In this embodiment, useful 7-10 memberedheterocyclo groups include 9-azabicyclo[3.3.1]nonan-3-yl, which can beunsubstituted or substituted as defined above. Further useful 7-10membered heterocyclo groups includeendo-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl,8-methyl-8-azabicyclo[3.2.1]octan-3-yl, andendo-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl. In one embodiment, R⁶ isany heterocycloalkyl as defined above and R⁵ is H. In anotherembodiment, R⁶ is any heterocycloalkyl as defined above and R⁵ is NH₂.In another embodiment, R⁶ is any heterocycloalkyl as defined above andR⁵ is C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁶ in G¹ isheterocyclo(C₁₋₄)alkyl, wherein the heterocyclo is selected from thegroup consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, andpiperazinyl, any of which is unsubstituted or substituted with one ormore substituents, typically 1, 2 or 3 substituents, selected from thegroup consisting of alkyl, hydroxy, hydroxyalkyl, cyano, aminocarbonyl,carboxy and alkoxycarbonyl, and R⁵ is as defined above for Formula I. Inone embodiment, R⁵ is H. In another embodiment, Compounds of theInvention are compounds of Formula I, wherein G is G¹, and where R⁶ inG¹ is 2-oxo-imidazolidin-1-yl(C₁₋₄alkyl, as specifically3-(2-oxo-imidazolidin-1-yl)propyl. In another embodiment, Compounds ofthe Invention are compounds of Formula I, wherein G is G¹, which isselected from the group consisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where R⁵ and R⁶ together with thenitrogen atom form a 5- or 6-membered heterocyclic ring having carbonatoms and 1 or 2 nitrogen atoms, wherein the heterocyclic ring isunsubstituted or substituted with one or more substituents, typically 1,2 or 3 substituents, each independently selected from the groupconsisting of oxo, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano.Useful substituents on the heterocyclic ring include oxo, C₁₋₆ alkyl,C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆alkoxycarbonyl, and cyano; and preferably oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, halo(C₁₋₄alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl,amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano. In one embodiment, R⁵ and R⁶ together withthe nitrogen atom form a 5-membered heterocyclic ring having carbonatoms and 1 or 2 nitrogen atoms, such as for example, pyrrolidin-1-yl orimidazolidin-1-yl, wherein the heterocyclic ring is unsubstituted orsubstituted as defined above. In another embodiment, R⁵ and R⁶ togetherwith the nitrogen atom form a 6-membered heterocyclic ring having carbonatoms and 1 or 2 nitrogen atoms, such as for example piperidin-1-yl orpiperazin-1-yl, wherein the heterocyclic ring is unsubstituted orsubstituted as defined above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹ having the structure:

wherein R¹⁰, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, amino,amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano; and typically each independently selectedfrom the group consisting of hydrogen, oxo, methyl, ethyl, propyl,isopropyl, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, amino,dimethylamino, diethylamino, methylaminomethyl, methylaminoethyl,dimethylaminomethyl, dimethylaminoethyl, aminocarbonyl, carboxy, cyano,methoxycarbonyl, and ethoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹ and G¹ is selected from the group consistingof

wherein R¹⁰, R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, amino,amino(C₁₋₄alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, aminocarbonyl, carboxy, C₁₋₄alkoxycarbonyl, and cyano; and typically each independently selectedfrom the group consisting of hydrogen, oxo, methyl, ethyl, propyl,isopropyl, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, amino,dimethylamino, diethylamino, methylaminomethyl, methylaminoethyl,dimethylaminomethyl, dimethylaminoethyl, aminocarbonyl, carboxy, cyano,methoxycarbonyl, and ethoxycarbonyl, provided that when G¹ is (iii),then R¹⁰ is other than hydrogen.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, where R⁵ and R⁶ together with the nitrogenatom to which they are attached form a heterocyclic ring selected fromthe group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, andpiperazinyl, which is unsubstituted or substituted with 1 or 2substituents each independently selected from the group consisting ofoxo, alkyl, hydroxy, hydroxyalkyl, cyano, aminocarbonyl, carboxy andalkoxycarbonyl; preferably each independently selected from the groupconsisting of oxo, C₁₋₄ alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, cyano,aminocarbonyl, carboxy and C₁₋₄ alkoxycarbonyl; and more preferably eachindependently selected from the group consisting of oxo, methyl, ethyl,propyl, iso-propyl, hydroxy, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, aminocarbonyl, methoxycarbonyl, and ethoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where G¹ is selected from the groupconsisting of

wherein R¹⁰ and R¹¹ are each independently selected from the groupconsisting of oxo, alkyl, hydroxy, hydroxyalkyl, cyano, aminocarbonyl,carboxy and alkoxycarbonyl; preferably each independently selected fromthe group consisting of oxo, C₁₋₄ alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,cyano, aminocarbonyl, carboxy and C₁₋₄ alkoxycarbonyl; and morepreferably each independently selected from the group consisting of oxo,methyl, ethyl, propyl, iso-propyl, hydroxy, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, aminocarbonyl, methoxycarbonyl, andethoxycarbonyl. In one embodiment, R¹⁰ is hydrogen or hydroxy and R¹¹ isas defined above. In another embodiment, R¹⁰ is hydrogen or hydroxy andR¹¹ is selected from the group consisting of aminocarbonyl and C₁₋₄alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where G¹ is

wherein R¹⁰ and R¹¹ are both hydrogen and R¹² is selected from the groupconsisting of oxo, alkyl, hydroxy, hydroxyalkyl, cyano, aminocarbonyl,carboxy and alkoxycarbonyl; preferably each independently selected fromthe group consisting of oxo, C₁₋₄ alkyl, hydroxy, hydroxy(C₁₋₄alkyl,cyano, aminocarbonyl, carboxy and C₁₋4 alkoxycarbonyl; and morepreferably each independently selected from the group consisting of oxo,methyl, ethyl, propyl, iso-propyl, hydroxy, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, aminocarbonyl, methoxycarbonyl, andethoxycarbonyl. In another embodiment, R¹² is oxo. In anotherembodiment, G¹ is 3-oxo-piperazinyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G¹, and where G¹ is selected from the groupconsisting of

wherein R¹¹ and R¹² are both hydrogen and R¹⁰ is selected from the groupconsisting of oxo, alkyl, hydroxy, hydroxyalkyl, cyano, aminocarbonyl,carboxy and alkoxycarbonyl; preferably each independently selected fromthe group consisting of oxo, C₁₋₄ alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,cyano, aminocarbonyl, carboxy and C₁₋4 alkoxycarbonyl; and morepreferably each independently selected from the group consisting of oxo,methyl, ethyl, propyl, iso-propyl, hydroxy, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, aminocarbonyl, methoxycarbonyl, andethoxycarbonyl. In one embodiment, G¹ is (i) and R¹⁰ is at the4-position of the piperidinyl ring.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where G is G²:

wherein p, R⁷, and R⁸ are as defined above for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where R⁷ in G² is —(CH₂)_(q)OH, whereinq is 0, 1, 2, 3, 4, or 5, and R⁸ is as defined above. Typically, q is 0,1, 2, or 3. More typically, q is 0, 1 or 2, and specifically q is 0or 1. In one embodiment, R⁷ is —(CH₂)_(q)OH as defined above and R⁸ ishydrogen. In another embodiment, R⁷ is —(CH₂)_(q)OH as defined above andR⁸ is a bond.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where R⁷ in G² is hydrogen, amino,alkylamino, dialkylamino or alkoxy. In one embodiment, R⁷ in G² ishydrogen. In another embodiment, R⁷ in G² is amino. In anotherembodiment, R⁷ in G² is alkylamino, preferably C₁₋₆ alkylamino, morepreferably C₁₋₄ alkylamino, such as methylamino, ethylamino,propylamino, and butylamino. In another embodiment, R⁷ in G² isdialkylamino, preferably di(C₁₋₆)alkylamino, and more preferablydi(C₁₋₄)alkylamino, such as dimethylamino, ethylmethylamino,diethylamino, methylpropylamino, ethylpropylamino, and dipropylamino. Inanother embodiment, R⁷ in G² is alkoxy, preferably C₁₋₆ alkoxy, and morepreferably C₁₋₄ alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, and tert-butoxy.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where R⁸ in G² is hydrogen.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where R⁸ in G² is a bond (—OR⁸ is ═O).

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where G² is —C(═O)NH₂.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G², and where G² is —C(═O)OH or—C(═O)O(C₁₋₄)alkyl, such as for example, —C(═O)OCH₃, —C(═O)OCH₂CH₃, or—C(═O)OCH₂CH₂CH₃.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where G is G³, that is a 5- or 6-membered heteroarylcontaining at least one nitrogen atom, wherein the heteroaryl isunsubstituted or substituted with one or more substituents, typically 1,2 or 3 substituents, each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, acyloxy, and cyano. Useful substituents for theheteroaryl group include C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆ acyloxy, andcyano; and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl, amino, amino(C₁₋₄)alkyl,C₁₋₂ alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl,aminocarbonyl, carboxy, C₁₋₄ acyloxy, and cyano. Useful 5- and6-membered heteroaryl groups include 5- and 6-membered heteroaryl groupshaving at least one nitrogen atom, such as pyrrolyl (e.g.,1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 1H-imidazol-2-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-imidazol-2-yl, and2H-imidazol-4-yl), 1,2,3-triazolyl (e.g., 1H-1,2,3-triazol-2-yl,1H-1,2,3-triazol-4-yl, and 1H-1,2,3-triazol-5-yl), 1,2,4-triazolyl(e.g., 1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl), thiazolyl(e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isooxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), pyridazinyl (e.g.,pyridazin-3-yl or pyridazin-4-yl), and pyrazinyl (e.g., pyrazin-2-yl andpyrazin-3-yl), which can be unsubstituted or substituted as definedabove.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G³, and where G³ is pyridinyl (pyridin-2-yl,pyridin-3-yl, or pyridin-4-yl), unsubstituted or substituted with one ormore substituents, typically 1, 2 or 3 substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, acyloxy, and cyano; andpreferably each independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆ acyloxy, andcyano; and more preferably each independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, halo(C₁₋₄alkyl,halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄alkyl, amino, amino(C₁₋₄)alkyl,C₁₋₂ alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl,aminocarbonyl, carboxy, C₁₋₄ acyloxy, and cyano. In another embodiment,Compounds of the Invention are compounds of Formula I, wherein G is G³and G³ is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl substituted withcyano or aminocarbonyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where G is G⁴, and G⁴ is —OR⁹, wherein R⁹ is alkyl, alkenyl,alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkyl,heteroarylalkyl, aryl or heteroaryl, wherein said aryl or heteroarylgroup is unsubstituted or substituted with one or more substituents,typically 1, 2 or 3 substituents, each independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, acyloxy, and cyano. In oneembodiment, R⁹ is alkyl, preferably C₁₋₆ alkyl, and more preferably C₁₋₄alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.In another embodiment, R⁹ is aryl, preferably C₆₋₁₄ aryl, and morepreferably C₆₋₁₂ aryl, such as phenyl, naphthyl and biphenyl,unsubstituted or substituted with one or more, preferably 1 or 2,substituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, acyloxy, and cyano. In another embodiment, R⁹ is heteroaryl,preferably 5- or 6-membered heteroaryl containing at least one nitrogenatom, unsubstituted or substituted with one or more substituents,typically 1, 2 or 3 substituents, each independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, acyloxy, and cyano. Useful 5-or 6-membered heteroaryl groups having at least one nitrogen atominclude pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl(e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,2H-imidazol-2-yl, and 2H-imidazol-4-yl), 1,2,3-triazolyl (e.g.,1H-1,2,3-triazol-2-yl, 1H-1,2,3-triazol-4-yl, and 1H-1,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g., 1H-1,2,4-triazol-3-yl and1H-1,2,4-triazol-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, andthiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, andpyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl),and pyrazinyl (e.g., pyrazin-2-yl and pyrazin-3-yl), which can beunsubstituted or substituted as defined above. Useful substituents forthe aryl and heteroaryl groups include C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl, di(C₁₋₄alkylamino(C₁₋₆)alkyl, aminocarbonyl, carboxy, C₁₋₆ acyloxy, and cyano;and preferably C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, amino, amino(C₁₋₄)alkyl,C₁₋₂ alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl,aminocarbonyl, carboxy, C₁₋₄ acyloxy, and cyano.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein G is G⁴, and where G⁴ is unsubstitutedpyridin-2-yloxy, pyridin-3-yloxy or pyridin-4-yloxy.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A¹ is an optionally substituted heteroaryl. In oneembodiment, A¹ is a 5-6 membered heteroaryl ring having at least onenitrogen atom. Typical heteroaryl groups for A¹ include 6-memberedheteroaryl groups having at least one nitrogen atom, such as pyridyl(pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyrimidinyl(pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or pyrimidin-6-yl),pyridazinyl (pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, orpyridazin-6-yl), and pyrazinyl (pyrazin-2-yl or pyrazin-3-yl). Inanother embodiment, Compounds of the Invention are compounds of FormulaI, where A¹ is unsubstituted or substituted pyridyl, such aspyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In another embodiment, A¹is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl optionally substitutedwith 1 or 2 substituents each independently selected from the groupconsisting of alkyl (for example, C₁₋₄ alkyl, such as methyl or ethyl),haloalkyl (for example, halo(C₁₋₄)alkyl, such as trifluoromethyl) andhalogen.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A¹ is an optionally substituted aryl. In oneembodiment, A¹ is unsubstituted phenyl. In another embodiment, A¹ isphenyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferably eachsubstituent is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each substituent is independentlyselected from the group consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl, hydroxy, nitro,amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido,C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄alkyl, C₁₋₄alkoxy, carboxy, and aminocarbonyl. Typically, the 1, 2, or 3substituents are each independently selected from the group consistingof C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl, hydroxy,nitro, amino, cyano, and C₁₋₄ alkoxy, and more typically are eachindependently selected from the group consisting of fluoro, bromo,trifluoromethyl, and cyano. In one embodiment, A¹ is phenyl substitutedat the 4-position. In this embodiment, the substituent is typicallyhalogen, cyano, or haloalkyl, such as trihaloalkyl, and specificallytrifluoromethyl. In one embodiment, A¹ is phenyl substituted with twosubstituents, which can be the same or different, at the 3- and4-positions. In this embodiment, the two substituents are independentlyselected from the group consisting of halogen, cyano and haloalkyl (suchas trihaloalkyl, and specifically trifluoromethyl). In one embodiment,A¹ is phenyl substituted with cyano and trifluoromethyl at the 3- and4-positions of the phenyl group, respectively.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where X is —O —, —S—, or —SO₂—. Typical compounds of thepresent invention include those where X is —O— or —S—. In anotherembodiment, Compounds of the Invention are those where X is —O—.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein A is A′ having the structure:

whereinX is —O, —S—, —SO—, —SO₂—, —CH₂—, or —NH—; and R¹³, R¹⁴, R¹⁵, and R¹⁶are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl; preferably each of R¹³, R¹⁴, R¹⁵, and R¹⁶ isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₆)alkyl, C₁₋₄alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino, thiol, C₁₋₆ acyloxy, azido,mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy, and aminocarbonyl; and morepreferably each of R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently selected fromthe group consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano,amide, carboxy(C₁₋₄alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄alkyl, C₁₋₄ alkoxy,carboxy, and aminocarbonyl. Typically, R¹³, R¹⁴, R¹⁵ and R¹⁶ are eachindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl, hydroxy, nitro,amino, cyano, and C₁₋₄ alkoxy. More typically, R¹³, R¹⁴, R¹⁵ and R¹⁶ areeach independently selected from the group consisting of hydrogen,fluoro, bromo, trifluoromethyl, and cyano. In this aspect of theinvention, compounds useful in the present invention are those where Xis —O— or —S—. In one embodiment, R¹³ and R¹⁴ are both hydrogen and R¹⁵and R¹⁶ are as defined above.

In another embodiment, Compounds of the invention are compounds ofFormula I, wherein A is A″ having the structure:

whereinR¹³, R¹⁴, R¹⁵, and R¹⁶ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R¹³, R¹⁴, R¹⁵,and R¹⁶ is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R¹³, R¹⁴, R¹⁵, and R¹⁶ isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄alkyl, C₁₋₂alkoxy(C₁₋₄alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above for A′. In one embodiment,R¹³ and R¹⁴ are both hydrogen and R¹⁵ and R¹⁶ are as defined above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″ and R¹-R⁴ are hydrogen, which Compounds of theInvention have the Formula II:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G is as defined in connection with Formula I, and R¹³,R¹⁴, R¹⁵, and R¹⁶ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹³, R¹⁴,R¹⁵ and R¹⁶ are those described above in connection with Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″, R¹-R⁴ are each hydrogen, and G is G¹, whichCompounds of the Invention have the Formula III:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above for FormulaI or II. Preferable definitions for R¹³, R¹⁴, R¹⁵ and R¹⁶ are thosedescribed above in connection with Formula I or II.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″, R¹-R⁴ are hydrogen, and G is G¹, whichCompounds of the Invention have the Formula IV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹³, R¹⁴, R¹⁵, and R¹⁶ are as defined in connectionwith Formula II.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″, R¹-R⁴ are hydrogen, and G is G², whichCompounds of the Invention have the Formula V:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹³, R¹⁴, R¹⁵, and R¹⁶ are as defined in connectionwith Formula I or II.

In another embodiment, Compounds of the Invention include compounds ofany of Formulae II-V, where R¹³ and R¹⁴ are both hydrogen and R¹⁵ andR¹⁶ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl(including monohydroxyalkyl and dihydroxyalkyl), hydroxy, nitro, amino,cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol,acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.Typically, R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, C₁₋₄ alkoxy, andcarboxy, and more typically R¹⁵ and R¹⁶ are each independently selectedfrom the group consisting of hydrogen, fluoro, bromo, trifluoromethyl,and cyano. In one embodiment, R¹³, R¹⁴, R⁵, and R¹⁶ each are hydrogen.In another embodiment, R¹³, R¹⁴ and R¹⁵ are hydrogen and R¹⁶ is alkyl,alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro,amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino,thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, or aminocarbonyl;preferably R¹⁶ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen,halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano,amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, or aminocarbonyl; and more preferably R¹⁶ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄alkyl, C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically,R¹⁶ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy. More typically, R¹⁶ is selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R¹⁶ is at the 4-position of the phenyl ring (i.e., atthe para-position). In this embodiment, the substituent is typicallyhalogen, specifically fluoro, cyano, or haloalkyl, such as trihaloalkyl,and specifically trifluoromethyl. In one embodiment, R¹³ and R¹⁴ areboth hydrogen and R¹⁵ and R¹⁶, which can be the same or different, areat the 3- and 4-positions of the phenyl ring (i.e., at the meta- andpara-positions). In this embodiment, R¹⁵ and R¹⁶ are typicallyindependently selected from the group consisting of halogen, cyano andhaloalkyl (such as trihaloalkyl, and specifically trifluoromethyl).

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹, R², R³, and R⁴ are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halogen, hydroxy, hydroxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, cyano,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkoxy, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylcarbonyloxy, carboxy, aminosulfonyl, C₁₋₆alkylsulfonylamino, (C₁₋₆ alkylsulfonylamino)(C₁₋₆) alkyl, ureido,(aminocarbonyl)(C₁₋₆) alkylamino, and (carboxy(C₁₋₆)alkyl)amino; morepreferably each is independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, hydroxy,hydroxy(C₁₋₄)alkyl, halo(C₁₋₄)alkyl, cyano, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, C₁₋₄ alkoxy, aminocarbonyl, C₁₋₄ alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, C₁₋₄ alkylcarbonylamino, C₁₋₄alkylcarbonyloxy, carboxy, aminosulfonyl, C₁₋₄ alkylsulfonylamino, (C₁₋₄alkylsulfonylamino)(C₁₋₄)alkyl, ureido, (aminocarbonyl)(C₁₋₄)alkylamino, and (carboxy(C₁₋₄)alkyl)amino; and more preferably each isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, hydroxy, hydroxy(C₁₋₄)alkyl,halo(C₁₋₂)alkyl, cyano, amino, C₁₋₂ alkylamino, di(C₁₋₂)alkylamino, C₁₋₂alkoxy, aminocarbonyl, C₁₋₂ alkylaminocarbonyl,di(C₁₋₂)alkylaminocarbonyl, C₁₋₂ alkylcarbonylamino, C₁₋₂alkylcarbonyloxy, carboxy, aminosulfonyl, C₁₋₂ (C₁₋₂ alkylsulfonylamino,alkyl sulfonylamino)(C₁₋₂) alkyl, ureido, (amino carbonyl)(C₁₋₂)alkylamino, and (carboxy(C₁₋₂)alkyl)amino.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹, R², R³, and R⁴ are each independently selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,butyl, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, carboxy, aminocarbonyl, amino,aminosulfonyl, methylsulfonylamino, ureido, —NHCH₂COOH, —NHCH₂CONH₂, and—CH₂NHSO₂Me. In another embodiment, Compounds of the Invention arecompounds of Formula I, where R¹, R², R³, and R⁴ are each hydrogen.

Optional substituents attached to aryl, phenyl, heteroaryl, cycloalkyl,and heterocyclo rings each take the place of a hydrogen atom that wouldotherwise be present in any position on the aryl, phenyl, heteroaryl,cycloalkyl and heterocyclo rings, respectively.

In another embodiment, Compounds of the Invention include:

-   N¹-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-N²,N²-dimethylethane-1,2-diamine;-   2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)ethanol;-   (S)-2-{4-[4-(4-fluorophenoxy)phenyl]quinazolin-2-ylamino}-3-hydroxy-propionamide;-   4-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-2-one;-   4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-amine;-   (S)-methyl    1-(4-(4-(4-fluorophenoxy)phenyl)-quinazolin-2-yl)-pyrrolidine-2-carboxylate;-   4-(4-(4-fluorophenoxy)phenyl)-2-(1-methylhydrazinyl)quinazoline;-   2-(4-ethylpiperazin-1-yl)-4-(4-(4-fluorophenoxy)phenyl)quinazoline;-   1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)piperidin-4-ol;-   2-(4-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-1-yl)ethanol;-   4-(4-(4-fluorophenoxy)phenyl)-2-(4-methylpiperazin-1-yl)quinazoline;-   (S)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-methyl    1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-4-hydroxy-pyrrolidine-2-carboxylate;-   N-(3-(1H-imidazol-1-yl)propyl)-4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-amine;-   N¹-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-N³,N³-dimethylpropane-1,3-diamine;-   4-(4-(4-fluorophenoxy)phenyl)-N-methylquinazolin-2-amine;-   (R)-3-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol;-   (S)-3-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol;-   (S)-2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)succinamide;-   4-(4-(4-fluorophenoxy)phenyl)-N-((1R,3S,55)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)quinazolin-2-amine;-   2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,3-diol;-   1-(2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)ethyl)imidazolidin-2-one;-   2-(1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)hydrazinyl)ethanol;-   2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)acetamide;

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

In another embodiment, Compounds of the Invention include:

-   4-(4-phenoxyphenyl)quinazoline-2-carboxamide;-   ethyl 4-(4-phenoxyphenyl)quinazoline-2-carboxylate;-   4-(4-phenoxyphenyl)quinazoline-2-carboxylic acid;-   (S)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)ethane-1,2-diol;    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

In another embodiment, Compounds of the Invention include:

-   2-ethoxy-4-(4-(4-fluorophenoxy)phenyl)-quinazoline;-   4-(4-(4-fluorophenoxy)phenyl)-2-(pyridin-2-yloxy)quinazoline;

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl,hexyl, heptyl, octyl, nonyl and decyl, among others. In one embodiment,useful alkyl groups are selected from straight chain C₁₋₆ alkyl groupsand branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, pentyl, 3-pentyl, hexyl, among others. In one embodiment,useful alkyl groups are selected from straight chain C₂₋₆ alkyl groupsand branched chain C₃₋₆ alkyl groups. Typical C₂₋₆ alkyl groups includeethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl,pentyl, 3-pentyl, hexyl, among others. In one embodiment, useful alkylgroups are selected from straight chain C₁₋₄ alkyl groups and branchedchain C₃₋₄ alkyl groups. Typical C₁₋₄ alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl.

Useful cycloalkyl groups are selected from saturated and partiallyunsaturated (containing one or two double bonds) cyclic hydrocarbongroups containing one to three rings having from three to twelve carbonatoms (i.e., C₃-C₁₂ cycloalkyl) or the number of carbons designated. Inone embodiment, the cycloalkyl has one or two rings. In anotherembodiment, the cycloalkyl is a C₃-C₈ cycloalkyl. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl and the like. Inone embodiment, the cycloalkyl group contains one double bond.Preferably, the cycloalkyl groups containing one double bond have fromfour to twelve carbon atoms (i.e., C₄-C₁₂ cycloalkenyl). Exemplarycycloalkyl groups containing one double bond include cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, among others. In another embodiment, the cycloalkyl groupcontains two double bonds. Preferably, the cycloalkyl groups containingtwo double bonds have from five to twelve carbon atoms (i.e., C₅-C₁₂cycloalkadienyl). Exemplary cycloalkyl groups having two double bondsinclude cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, cyclononadienyl, cyclodecadienyl, among others.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by one or more fluorine, chlorine, bromine or iodineatoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by one or more hydroxy groups, such asmonohydroxyalkyl and dihydroxyalkyl groups (e.g., hydroxymethyl,hydroxyethyl, hydroxypropyl and hydroxybutyl groups, and especiallyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀)haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,trifluoromethoxy, and 2,2,2-trifluoroethoxy).

Useful (cycloalkyl)alkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with any of the above-mentioned cycloalkylgroups (e.g., cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferablyphenyl, naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned aryl groups (e.g.,benzyl, phenethyl, and the like).

Useful aralkyloxy groups include oxygen substituted by one of theabove-mentioned arylalkyl groups (e.g., benzyloxy).

The term “heteroaryl” or “heteroaromatic” as employed herein refers togroups having 5 to 14 ring atoms, with 6, 10 or 14 it electrons sharedin a cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen or sulfur heteroatoms, or 4 nitrogen atoms. Examples ofheteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include thienyl (e.g.,thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl(e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl).

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₄₀alkyl groups substituted by any of the above-mentioned heteroaryl groups(e.g., imidazol-1-ylmethyl, imidazol-1-ylethyl, imidazol-1-ylpropyl,pyridin-2-ylmethyl, pyridin-2-ylethyl, pyridin-3-ylmethyl,pyridin-3-ylethyl, pyridin-4-ylmethyl, pyridin-4-ylethyl, and the like).

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or wholly or partially unsaturated 3-7 membered monocyclic, or7-10 membered bicyclic ring system, which consist of carbon atoms andfrom one to four heteroatoms independently selected from the groupconsisting of O, N, and S, wherein the nitrogen and sulfur heteroatomscan be optionally oxidized, the nitrogen can be optionally quaternized,and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. In one embodiment, the 3- to7-membered monocyclic heterocyclic ring is either a saturated, orunsaturated non-aromatic ring. A 3-membered heterocyclo can contain upto 1 heteroatom, a 4-membered heterocyclo can contain up to 2heteroatoms, a 5-membered heterocyclo can contain up to 4 heteroatoms, a6-membered heterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atom.Examples include, but are not limited to, pyrrolidinyl, piperidinyl,2-oxo-piperidinyl, piperazinyl, morpholinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl,isoxazolidinyl, 3-oxo-isoxazolidinyl, tetrahydrothienyl, imidazolidinyl,2-oxoimidazolidinyl, hexahydropyrimidinyl,endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl,8-methyl-8-azabicyclo[3.2.1]octan-3-yl,endo-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl,benzodiazepines, and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups (e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-1-yl)methyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,(2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl,(2-oxo-imidazolidin-1-yl)propyl, and the like).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with an amino group.

Useful diaminoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with two amino groups.

Useful alkylamino and dialkylamino groups are —NHR¹⁸ and —NR¹⁸R¹⁹,respectively, wherein R²⁰ and R²¹ are each independently selected from aC₁₋₁₀ alkyl group.

Useful hydroxyalkylamino groups are —NHR¹⁹, wherein R¹⁹ is any of theabove-mentioned hydroxyalkyl groups.

Useful alkylaminoalkyl and dialkylaminoalkyl groups are any of theabove-mentioned C₁₋₁₀alkyl groups substituted by any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

The term “carbonyl” means —C(═O)—.

The term “oxo” means ═O.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned C₁₋₁₀ alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, and propoxycarbonyl).

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

As used herein, the term “aminosulfonyl” refers to —SO₂NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” refers to a radical of formula—C(═O)NR²OR²¹, wherein R²⁰ and R²¹ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and—CON(H)Ph and the like

Useful (aminocarbonyl)alkyl groups are any of the above-mentioned C₁₋₁₀alkyl groups substituted by one or more, typically 1 or 2, aminocarbonylgroups, such as aminocarbonylmethyl or 1,2-di(aminocarbonyl)ethyl.

Useful (aminocarbonyl)alkylamino groups are any of the above-mentioned(aminocarbonyl)alkyl groups attached to an amino nitrogen, such as(aminocarbonyl)methylamino.

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R²⁰ is H and R²¹ is C₁₋₁₀alkyl or where R²⁰ and R²¹ are each independently selected from a C₁₋₁₀alkyl group, respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR²²R²³, wherein R²² and R²³ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, —SO₂N(H)Phand the like.

As used herein, the term “alkylsulfonylamino” refers to —SO₂N(H)R²⁴,wherein R²⁴ is any of the above-mentioned C₁₋₁₀ alkyl groups.

As used herein, the term “(alkylsulfonylamino)alkyl” refers to any ofthe above-mentioned C₁₋₁₀ alkyl groups substituted with any of theabove-mentioned alkylsulfonylamino groups.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by —COOH.

Useful (carboxyalkyl)amino groups are —NHR²⁵, wherein R²⁵ is any of theabove-mentioned carboxyalkyl groups.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, and mercapto(C₁₋₆)alkyl groups mentioned above. Preferredoptional substituents include halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy,halo(C₁₋₆)alkoxy, and amino.

The present invention disclosed herein is also meant to encompassprodrugs of any of the disclosed compounds. As used herein, prodrugs areconsidered to be any covalently bonded carriers that release the activeparent drug in vivo. In general, such prodrugs will be functionalderivatives of compounds of any of Formulae I-V which will be readilyconvertible in vivo, e.g., by being metabolized, into the requiredcompound of Formulae I-V. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described in, forexample, Design of Prodrugs, H. Bundgaard ed., Elsevier (1985); “Drugand Enzyme Targeting, Part A,” K. Widder et al. eds., Vol. 112 inMethods in Enzymology, Academic Press (1985); Bundgaard, “Design andApplication of Prodrugs,” Chapter 5 (pp. 113-191) in A Textbook of DrugDesign and Development, P. Krogsgaard-Larsen and H. Bundgaard eds.,Harwood Academic Publishers (1991); Bundgaard et al., Adv. Drug DeliveryRevs. 8:1-38 (1992); Bundgaard et al., J. Pharmaceut. Sci. 77:285(1988); and Kakeya et al., Chem. Pharm. Bull. 32:692 (1984).Non-limiting examples of prodrugs include esters or amides of compoundsof any of Formulae I-V having hydroxyalkyl or aminoalkyl as asubstituent, and these may be prepared by reacting such parent compoundswith anhydrides such as succinic anhydride.

The present invention disclosed herein is also intended to encompass anyof the disclosed compounds being isotopically-labelled (i.e.,radiolabeled) by having one or more atoms replaced by an atom having adifferent atomic mass or mass number. Examples of isotopes that can beincorporated into the disclosed compounds include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively, and preferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeledcompounds of the present invention can be prepared by methods known inthe art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their ability to bind to thesodium channel. For example, one use of the labeled compounds of thepresent invention is the characterization of specific receptor binding.Another use of a labeled compound of the present invention is analternative to animal testing for the evaluation of structure-activityrelationships. For example, the receptor assay may be performed at afixed concentration of a labeled compound of the invention and atincreasing concentrations of a test compound in a competition assay. Forexample, a tritiated compound of any of Formulae I-V can be prepared byintroducing tritium into the particular compound, for example, bycatalytic dehalogenation with tritium. This method may include reactinga suitably halogen-substituted precursor of the compound with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration or cure, including preemptive and palliative treatment. Theterm “R⁸ is a bond” for —OR⁸ refers to the formation of an ═O group withthe carbon atom to which the —OR⁸ group is attached.

When numeric ranges are provided for parameters, e.g. the parameterbeing 0-5, then it is meant that all of the numbers inbetween are alsoencompassed, such as q is 0-5 means that q is selected from 0, 1, 2, 3,4, or 5.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present invention with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present invention is 2:1, 1:1 or 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of any of Formulae I-V may be present as solvatedforms with a pharmaceutically acceptable solvent, such as water,methanol, ethanol, and the like, and it is intended that the inventionincludes both solvated and unsolvated forms of compounds of any ofFormulae I-V. One type of solvate is a hydrate. A “hydrate” relates to aparticular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet a.l, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun.: 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a compound of any of Formulae I-V in a desiredsolvent (organic, water, or a mixture thereof) at temperatures aboveabout 20° C. to about 25° C., then cooling the solution at a ratesufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques such as infraredspectroscopy can be used to confirm the presence of the solvent in acrystal of the solvate.

Since compounds of Formulae I-V are modulators, in particular blockersof sodium (Na⁺) channels, a number of diseases and conditions mediatedby sodium ion influx can be treated by employing these compounds. Thepresent invention is thus directed generally to a method for treating adisorder responsive to the blockade of sodium channels in an animalsuffering from, or at risk of suffering from, said disorder, said methodcomprising administering to the animal an effective amount of a compoundrepresented by any of defined Formulae I-V, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

The present invention is further directed to a method of modulating, inparticular blocking, sodium channels in an animal in need thereof, saidmethod comprising administering to the animal a modulating-effectiveamount of at least one compound represented by any of defined FormulaeI-V, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

More specifically, the present invention provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, pain (e.g.,acute pain, chronic pain, which includes but is not limited toneuropathic pain, postoperative pain and inflammatory pain, or surgicalpain), migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, theinvention provides a method of treating pain. In another embodiment, thetype of pain is chronic pain. In another embodiment, the type of pain isneuropathic pain. In another embodiment, the type of pain ispostoperative pain. In another embodiment, the type of pain isinflammatory pain. In another embodiment, the type of pain is surgicalpain. In another embodiment, the type of pain is acute pain. In anotherembodiment, the treatment of pain (e.g., chronic pain, such asneuropathic pain or inflammatory pain, acute pain or surgical pain) ispreemptive. In another embodiment, the treatment of pain is palliative.In each instance, such method of treatment requires administering to ananimal in need of such treatment an amount of a compound of the presentinvention that is therapeutically effective in achieving said treatment.In one embodiment, the amount of such compound is the amount that iseffective as to block sodium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs, at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiences. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-V, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating a disorder responsive to the blockade of sodiumchannels (e.g., any of the disorders listed above) in an animalsuffering from said disorder.

Furthermore, the present invention is directed to a compound representedby any of Formulae I-V, or a pharmaceutically acceptable salt, prodrugor solvate thereof, for use in modulating, in particular blocking,sodium channels in an animal in need thereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-V, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament, in particular a medicament for modulating, in particularblocking, sodium channels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention can be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I can be prepared as shown in Schemes 1-6below. Additional methods of synthesis are described and illustrated inthe working examples set forth below.

wherein R¹, R², R³, R⁴, and A are as defined above for Formula I, and R′and R″ are each independently selected from the group consisting ofhydrogen and C₁₋₆ alkyl.

wherein R¹, R², R³, R⁴, R⁵, R⁶, and A are as defined above for FormulaI. Ref. 1: (a) Eiichi YAMAMOTO et al., U.S. Pat. Appl. Publ. No.2009/0062539; (b) Kazuhiro Yokoyama et al., Bioorg. Med. Chem. 17:64-73(2009).

wherein R¹, R², R³, R⁴, R¹⁵, and R¹⁶ are as defined above for Formula I,and R′ and R″ are each independently selected from the group consistingof hydrogen and C₁₋₄ alkyl.

wherein R¹, R², R³, R⁴, and A are as defined above for Formula I.

wherein R¹, R², R³, R⁴, and A are as defined above for Formula I.

wherein R⁵, R⁶, and A are as defined above for Formula I.

Testing of Compounds

Compounds of the present invention were assessed by sodium mobilizationand/or electrophysiological assays for sodium channel blocker activity.One aspect of the present invention is based on the use of the compoundsherein described as sodium channel blockers. Based upon this property,compounds of the present invention are considered useful in treating acondition or disorder responsive to the blockade of sodium ion channels,e.g., stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, dystonia, tremor, mental retardation, autism, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. Compounds of the Inventionare also expected to be effective in treating pain, such as acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain and inflammatory pain, or surgical pain.

More specifically, the present invention is directed to compounds ofFormulae I-V that are blockers of sodium channels. According to thepresent invention, those compounds having useful sodium channel blockingproperties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8 and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 10 μM or less,about 5 μM or less, or about 1 μM or less, in the sodium mobilizationand/or electrophysiological assays described herein. In certainembodiments, Compounds of the Invention exhibit an IC₅₀ for Na_(v)1.7 of100 μM or less, e.g., about 50 μM or less, about 10 μM or less, about 5μM or less, or about 1 μM or less, about 0.5 μM or less, or about 0.1 μMor less. Compounds of the Invention can be tested for their Na⁺channelblocking activity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In Vitro Assay Protocols FLIPR® Assays:

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_(—)002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J. Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was, constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibioticwas omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO4 and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3,333 μM, 1,111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism 4.0 Program (available fromGraphPad Software, San Diego, Calif.) to determine the IC₅₀ value forthe test article. At least one standard reference compound was evaluatedduring each experiment.

FLIPR® or FLIPR^(TETRA)® sodium dye assay with KCl and test articlepre-incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate was then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure was very similar, though optimaldensities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)first, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μL/well. The cells wereincubated at 25° C. in the dark for 30 mM. before their fluorescence wasmeasured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions are filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® membrane potential assay with KCl and testarticle pre-incubation: Cells are prepared by plating the recombinantHEK293 cells or other host cells expressing either recombinant ornon-recombinant, native, Na_(v)1.7 alpha subunit, alone or incombination with various beta and gamma subunits at a density of ˜40,000cells/well into a 96-well black, clear-bottom, PDL-coated plate. Theassay can be adapted to 384-well or 1,536-well format, if desired, usingproportionately less cells and media. The plate is then incubated ingrowth media, with or without selective antibiotic, overnight at 37° C.at 5% CO₂, 95% humidity, in preparation for the assay (see, e.g.,Benjamin et. al., J. Biomol. Screen 10(4):365-373 (2005)). For screensand counter-screens of other voltage-gated sodium channels, the assayprotocol is similar, though optimal densities of cells, media andsubsequent assay components can be fine-tuned for the particular cellline or sodium channel isoform being tested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® sodium dye assay without KCl and test articlepre-incubation: Cells are prepared by plating the recombinant HEK293cells or other host cells expressing either recombinant ornon-recombinant, native, Na_(v)1.7 alpha subunit, alone or incombination with various beta and gamma subunits at a density of ˜40,000cells/well into a 96-well black, clear-bottom, PDL-coated plate. Theassay can be adapted to 384-well or 1,536-well format, if desired, usingproportionately less cells and media. The plate is then incubated ingrowth media, with or without selective antibiotic, overnight at 37° C.at 5% CO₂, 95% humidity, in preparation for the assay. Forcounter-screens of other voltage-gated sodium channels, the procedure isvery similar, though optimal densities of cells, media and subsequentassay components can be fine-tuned for the particular cell line orisoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 from a freshly diluted sample of the stock (now at 4×concentration) in the assay buffer. The cells are incubated at 37° C. inthe dark for 30-60 mM. before their fluorescence is measured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells: The hNa_(v)1.7 expressing HEK-293 cells were plated on 35 mmculture dishes pre-coated with poly-D-lysine in standard DMEM culturemedia (Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂incubator at 37° C. Cultured cells were used approximately 12-48 hoursafter plating.

Electrophysiology:

On the day of experimentation, the 35 mm dish was placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system was used to apply test solutionsdirectly to the cell under evaluation. This system consists of an arrayof glass pipette glass connected to a motorized horizontal translator.The outlet of the shooter was positioned approximately 100 μm from thecell of interest.

Whole cell currents were recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealswere formed and the whole-cell configuration was established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 were recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MΩ when filled with pipette solution and seriesresistance (<5 MΩ) was compensated 75-80%. Signals were sampled at 50kHz and low pass filtered at 3 kHz.

Voltage protocols:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols were run to establish the 1) test potential, 2)holding potential, and 3) the conditioning potential for each cell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol was run to determine the potential at which themaximal current (I_(max)) is elicited. This potential was the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels were in the inactivated state, a standard steady-stateinactivation (SSIN) protocol was run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse, V_(t), to V_(max). This protocol alsopermitted determination of the holding potential at which all channelsare in the resting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) was generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell wasdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolwas repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline was established, the test compound was appliedand block of the current elicited by the test pulse assessed. In somecases, multiple cumulative concentrations were applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound was attempted by superfusing with control solution oncesteady-state block was observed. An estimate of the K_(i) was calculatedas follows:

K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) was determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents was as follows. First, the standard current-voltagerelationship was tested by pulsing the cell from the holding voltage(V_(h)) of −120 mV by a series of 5 msec long square-shaped test pulsesincrementing in +10 mV steps over the membrane voltage range of −90 mVto +60 mV at the pace of stimulation of 0.5 Hz. This proceduredetermines the voltage that elicits the maximal current (V_(max)).Second, V_(h) was re-set to −120 mV and a steady-state inactivation(SSIN) curve was taken by the standard double-pulse protocol: 100 msdepolarizing pre-pulse was incremented in steps of +10 mV (voltage rangefrom −90 mV to 0 mV) immediately followed by the 5 ms long test pulse to−10 mV at the pace of stimulation of 0.2 Hz. This procedure determinesthe voltage of full inactivation (V_(full)). Third, the cell wasrepeatedly stimulated with the following protocol, first in the absenceof the test compound then in its presence. The protocol consisted ofdepolarizing the cell from the holding potential of −120 mV to theV_(full) value for 4.5 seconds then repolarizing the cell to the holdingpotential for 10 ms before applying the test pulse to the V_(max) for 5ms. The amount of inhibition produced by the test compound wasdetermined by comparing the current amplitude elicited by the test pulsein the absence and presence of the compound.

In a further alternative, the voltage clamp protocol to examineliNa_(v)1.7 currents was as follows. After establishing the whole-cellconfiguration in voltage clamp mode, two voltage protocols were run toestablish: 1) the holding potential; and 2) the test potential for eachcell.

Resting block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol was run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (Vhi) was 20 mV morehyperpolarized than the first potential where inactivation was observedwith the inactivation protocol.

From this holding potential a standard I-V protocol was run to determinethe potential at which the maximal current (Imax) is elicited. Thispotential was the test potential (Vt).

The compound testing protocol was a series of 10 ms depolarizations fromthe Vhi (determined from the SSIN) to the Vt (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline wasestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides ˜50% block) wasapplied and block of the current assessed.

Washout of the compound was attempted by superfusing with controlsolution once steady-state block was observed. The fractional responsewas calculated as follows:

K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of inactivated channels:

To assess the block of inactivated channels the holding potential wasdepolarized such that 20-50% of the current amplitude was reduced whenpulsed to the same Vt as above. The magnitude of this depolarizationdepends upon the initial current amplitude and the rate of current lossdue to slow inactivation. This was the second holding potential (Vh2).The current reduction was recorded to determine the fraction ofavailable channels at this potential (h).

h=I@Vh2/Imax.  Eq. 4

At this membrane voltage a proportion of channels was in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents were elicited by 10 ms voltage steps from Vh2 to Vtevery 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound was applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses were measuredwith respect to a projected baseline to determine K_(app).

K _(app)=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, wereused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:

K _(i)=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Solutions and chemicals:

For electrophysiological recordings the external solution was eitherstandard, DMEM supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contained (in mM):NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds were prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO didnot affect sodium currents. Vehicle solution used to establish base linewas also contacting 0.3% DMSO.

Data analysis: Data was analyzed off-line using Clampfit software(pClamp, v. 8; Axon Instruments) and graphed using GraphPad Prizm (v.4.0) software.

In Vivo Assay for Pain

The compounds of the present invention can be tested for theirantinociceptive activity in the formalin model as described in Hunskaaret al., J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIHmice (20-30 g; Harlan, San Diego, Calif.) can be used in allexperiments. Food is withdrawn on the day of experiment. Mice are placedin Plexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period, mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (for example, 10% Tween-80 or 0.9% saline, and otherpharmaceutically acceptable vehicles) as control. Fifteen minutes afterthe i.p. dosing, and 30 minutes after the p.o. dosing mice are injectedwith formalin (20 pt of 5% formaldehyde solution in saline) into thedorsal surface of the right hind paw. Mice are transferred to thePlexiglass jars and monitored for the amount of time spent licking orbiting the injected paw. Periods of licking and biting are recorded in5-minute intervals for 1 hour after the formalin injection. Allexperiments are done in a blinded manner during the light cycle. Theearly phase of the formalin response is measured as licking/bitingbetween 0-5 minutes, and the late phase is measured from 15-50 minutes.Differences between vehicle and drug treated groups can be analyzed byone-way analysis of variance (ANOVA). A P value <0.05 is consideredsignificant. Compounds are considered to be efficacious for treatingacute and chronic pain if they have activity in blocking both the earlyand second phase of formalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 hours before dosing. A controlgroup acts as a comparison to rats treated with a compound of FormulaeI-V. The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of the compounds of Formulae I-V on the treatmentof inflammatory pain the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).The left hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. 24 hour post injection, the animal is assessed forresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), or to noxious thermal stimuli by determining the pawwithdrawal latency (PWL), as described below. Rats are then administereda single injection of either a test compound or 30 mg/Kg of a positivecontrol compound (indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (admin). Percentage reversal of hyperalgesia for eachanimal is defined as:

${reversal} = {\frac{\begin{bmatrix}{( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T\mspace{14mu} {or}\mspace{14mu} P\; W\; L} ) -} \\( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T\mspace{14mu} {or}\mspace{14mu} P\; W\; L} )\end{bmatrix}\mspace{14mu} \%}{\begin{bmatrix}{( {{baseline}\mspace{14mu} P\; W\; T\mspace{14mu} {or}\mspace{14mu} P\; W\; L} ) -} \\( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T\mspace{14mu} {or}\mspace{14mu} P\; W\; L} )\end{bmatrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anaesthesia.Following induction of anaesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover fromanaesthesia. Animals are then returned to their home cages untilbehavioral testing begins. The animals are assessed for response tonoxious mechanical stimuli by determining PWT, as described below, priorto surgery (baseline), then immediately prior to and 1, 3, and 5 hoursafter drug administration for rear paw of the animal. Percentagereversal of neuropathic hyperalgesia is defined as:

${reversal} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack \mspace{14mu} \%}{\lbrack {( {{baseline}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anaesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a compound of FormulaeI-V for the left rear paw of the animal. The animals can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In vivo Assay for Anticonvulsant Activity

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocorneae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response. A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

Pharmaceutical Compositions

Although a Compound of the Invention can be administered to a mammal inthe form of a raw chemical without any other components present, thecompound is preferably administered as part of a pharmaceuticalcomposition containing the compound combined with a suitablepharmaceutically acceptable carrier. Such a carrier can be selected frompharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a Compound of the Invention is combinedwith a pharmaceutically acceptable carrier. In a preferred embodiment,the compound is present in the composition in an amount that iseffective to achieve its intended therapeutic purpose. While individualneeds may vary, a determination of optimal ranges of effective amountsof each compound is within the skill of the art. Typically, a compoundcan be administered to a mammal, e.g., a human, orally at a dose of fromabout 0.0025 to about 1500 mg per kg body weight of the mammal, or anequivalent amount of a pharmaceutically acceptable salt, prodrug, orsolvate thereof, per day to treat, prevent or ameliorate the particulardisorder. A useful oral dose of a Compound of the Invention administeredto a mammal is from about 0.0025 to about 50 mg per kg body weight ofthe mammal, or an equivalent amount of the pharmaceutically acceptablesalt, prodrug, or solvate thereof. For intramuscular injection, the doseis typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable salt,prodrug or solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a compound of the presentinvention. In one embodiment, the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A Compound of the Invention (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein. In one embodiment, a Compound of theInvention is administered concurrently with a second therapeutic agent;for example, a single composition comprising both an effective amount ofa compound of any of Formulae I-V, and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentinvention further provides a pharmaceutical composition comprising acombination of a compound of the present invention, the secondtherapeutic agent, and a pharmaceutically acceptable carrier.Alternatively, a first pharmaceutical composition comprising aneffective amount of a compound of any of Formulae I-V and a secondpharmaceutical composition comprising an effective amount of the secondtherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a Compound of the Invention isadministered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, the Compoundof the Invention is administered while the second therapeutic agentexerts its therapeutic effect, or the second therapeutic agent isadministered while the compound of the present invention exerts itstherapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopa/levodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating or preventingdementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs suchas thioridazine and haloperidol; and antidepressant drugs such as thosegiven below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which itself will be known in view of theinstant disclosure, for example, by means of conventional mixing,granulating, dragee-making, dissolving, extrusion, or lyophilizingprocesses. Thus, pharmaceutical compositions for oral use can beobtained by combining the active compound with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1 Ethyl 4-(4-phenoxyphenyl)quinazoline-2-carboxylate(3) 4-(4-phenoxyphenyl)quinazoline-2-carboxylic acid (4)4-(4-phenoxyphenyl)quinazoline-2-carboxamide (5)

(a) A mixture of compound 1 (1 g, 1.0 eq., Syntech Dev.), compound 2 (1g), K₂CO₃ (2 g) and bis(triphenylphosphine)palladium(II) chloride(Aldrich, 0.1 eq.), in 100 mL of EtOH/water (99/1) was heated at 50° C.for 24 hours. After cooling to room temperature, the reaction wasquenched with water (100 mL), and extracted with CHCl₃ (2×400 mL). Theorganic layers were combined and concentrated, and the residue wasdissolved in EtOH (100 mL) at room temperature, and then H₂SO₄ (2 mL)was added. The resulting mixture was heated at 60° C. for 14 hours. Thesolvent was removed and the residue was purified by column (Silica gel,CHCl₃) to obtain compound 3 as a white solid (1.2 g, yield 80%): ¹H-NMR(400 MHz, CDCl₃): δ 8.33 (d, 1H, 8.3 Hz), 8.25 (d, 1H, 8.3 Hz), 8.01(dt, 1H, 1.3 & 8.1 Hz), 7.86 (d, 2H, 8.7 Hz), 7.74 (dt, 1H, 1.3 & 8.1Hz), 7.39-7.44 (m, 2H), 7.17-7.21 (m, 3H), 7.11-7.14 (m, 2H), 4.61 (q,2H, 7.0 Hz), 1.51 (t, 3H, 7.0 Hz); LC/MS: ink=371.4 [M+H]+(Calc: 370.4).

(b) A mixture compound 3 (0.2 g) and NH₃ (7N in MeOH, 10 mL) was heatedto 50° C. for 14 hours. After cooling to room temperature, the reactionwas titrated with water, and the solid was collected, washed with waterand dried to obtain compound 5 as a white solid (0.11 g, yield 60%):¹H-NMR (400 MHz, CDCl₃): δ 8.34 (d, 1H, 8.3 Hz), 8.25 (d, 114, 8.3 Hz),8.15 (br, 1H, NH), 8.01 (dt, 1H, 1.3 & 8.1 Hz), 7.86 (d, 211, 8.9 Hz),7.73 (dt, 1H, 1.3 & 8.1 Hz), 7.39-7.44 (m, 2H), 7.13-7.23 (m, 5H), 5.99(br, 1H, NH); LC/MS: m/z=342.5 [M+H]+(Calc: 341.4).

(c) A mixture of compound 3 (0.2 g) in EtOH (5 mL) was treated with NaOH(1.5 mL, 2N aqueous) at 40° C. for 10 hours. The solvent was removed,and the residue was dissolved in TCM (20 mL) and neutralized with HCl(0.2N 10 mL) at 0° C. The organic layer was washed with brine, andconcentrated to afford compound 4 as a white solid (80 mg, yield 44%):¹H-NMR (400 MHz, CD₃OD): δ 8.25-8.31 (m, 2H), 8.06 0-8.11 (m, 1H),7.98-8.02 (m, 2H), 7.79-7.83 (m, 1H), 7.5-7.55 (m, 2H), 7.21-7.31 (m,5H); LC/MS: m/z=343.5 [M+H]+(Calc: 342.4).

Example 2(S)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)ethane-1,2-diol (10)

(a) Water (3 mL) was added to a mixture of compound 6 (0.5 g, 1.0 eq.,AstaTech, Inc.), compound 7 (0.7 g), Pd(Ph₃P)₄ (0.3 g), K₂CO₃ (0.4 g)and toluene (10 mL) under nitrogen, and the resulting mixture was shakenat 95° C. for 18 hours. Toluene (100 mL) and water (40 mL) were added tothe reaction mixture. The organic layer was separated and purified bycolumn (TCM/Hexanes 7/4) to obtain compound 8 as a yellow solid (0.5 g,yield 86%): ¹H-NMR (400 MHz, CDCl₃): δ 8.09 (d, 1H, 8.9 Hz), 7.97 (d,111, 8.6 Hz), 7.84-7.88 (m, 1H), 7.71 (d, 2H, 8.1 Hz), 7.53-7.57 (m,1H), 7.01-7.09 (m, 6H).

(b) A mixture of compound 8 (0.2 g, 0.57 mmol, 1.0 eq.), vinylboronicacid pinacolester (1.2 eq., Aldrich), TBAF (1.0 mL, 1M in THF), 4 mLTHF/1 mL

DMF and Pd(dppf)Cl₂.CH₂Cl₂ (0.1 eq.) was flushed with argon, then,shaken at 90° C. for 2 hours. EtOAc (40 mL) and water (20 mL) were addedto the reaction mixture, the organic layer was separated, concentratedand purified by column (TCM/Hexanes 1/1) to give compound 9 as a whitesolid (0.1 g): LC/MS: m/z=343.2 [M+H]+(Calc: 342.4).

(c) AD-mix-α (0.5 g) was added to a mixture of compound 9 (0.1 g) in 10mL of t-BuOH/water (1/1) at 0° C. The resulting mixture was shaken atroom temperature for 24 hours. EtOAc (40 mL) and water (20 mL) wereadded to the reaction mixture, the organic layer was separated,concentrated and purified by column (silica gel, TCM/MeOH 10/0.5) toafford the title compound 10 as a white solid (80 mg, yield 70%): ¹H-NMR(400 MHz, CDCl₃): δ 8.21 (d, 1H, 8.3 Hz), 8.13 (d, 1H, 8.3 Hz),7.95-7.99 (m, 1H), 7.82 (d, 2H, 8.9 Hz), 7.64-7.68 (m, 1H), 7.12-7.18(m, 6H), 5.08-5.11 (m, 1H), 4.8 (br, 2H, —OH), 4.12-4.18 (m, 2H); LC/MS:m/z=377.0 [M+H]+(Calc: 376.4).

Example 3 Synthesis of Compounds 13a-13z

12a: H-SER-NH₂ HCL (ALDRICH); 12b: PIPERAZIN-2-ONE (Tyger ScientificInc.); 12c: ETHANOLAMINE (ALDRICH); 12d: N,N-DIMETHYLETHYLENEDIAMINE(ALDRICH); 12e: NH₃ (7N˜in MeOH, ALDRICH); 12f: L-PROLINE METHYL ESTERHYDROCHLORIDE (ALDRICH); 12 g: METHYLHYDRAZINE (ALDRICH); 12 h:N-ETHYLPIPERAZINE (ALDRICH); 12i: 4-HYDROXYPIPERIDINE (ALDRICH); 12j:N-(2-HYDROXYETHYL)PIPERAZINE (ALDRICH); 12k: 1-METHYLPIPERAZINE(ALDRICH); 12l: H—PRO—NH₂ L-PROLINAMIDE (ACROS); 12m: H-HYP-OME HCL(ALDRICH); 12n: METHYLAMINE (ALDRICH); 12o: N-(3-AMINOPROPYL)IMIDAZOLE(ALDRICH); 12p: N,N-DIMETHYL-1,3-PROPANEDIAMINE (ACROS); 12q:(R)-3-AMINO-1,2-PROPANEDIOL (TCI-US); 12r: (S)-3-AMINO-1,2-PROPANEDIOL(TCI-US); 12s: H-ASN—NH2 HCL (SIGMA); 12t:ENDO-9-METHYL-9-AZABICYCLO[3.3.1]-NONAN-3-AMINE (Trylead ChemicalTechnology Co., Ltd.); 12u: 2-AMINO-1,3-PROPANEDIOL (FLUKA); 12v:1-(2-AMINOETHYL)-2-IMIDAZOLIDONE (OAKWOOD); 12w: 2-HYDROXYETHYLHYDRAZINE(ALDRICH); 12x: GLYCINAMIDE HYDROCHLORIDE (ALDRICH); 12y: ETHANOL(ALDRICH); 12z: 2-HYDROXYPYRIDINE (ALDRICH).

General procedure for the preparation of compounds 13a-z: A mixture ofcompound 11 (0.2 g, 1.0 eq.), RH (12a-z, 1.05 eq.), wherein R is NR⁵R⁶or OR⁹, K₂CO₃ (2 eq.) and TEA (2 eq.) in 3 mL of DMF was shaken at 100°C. for 24 hours. Water (5 mL) and EtOAc (30 mL) were added to thereaction mixture. The organic layer was separated, concentrated andpurified by column (TCM/MeOH 10/0.2 to 10/5) to obtain compounds 13a-zin 20 to 90% yield.

(S)-2-{4-[4-(4-Fluoro-phenoxy)-phenyl]-quinazolin-2-ylamino}-3-hydroxy-propionamide(13a,yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.81 (d, 1H, 7.8 Hz),7.61-7.66 (m, 3H), 7.54 (d, 1H, 8.5 Hz), 7.15-7.19 (m, 1H), 7.01-7.06(m, 6H), 4.65 (t, 1H, 4.8 Hz), 3.93 (dd, 1H, 5.0 & 10.9 Hz), 3.85 (dd,1H, 4.8 & 11.0 Hz); LC/MS: m/z=419.2 [M+H]+(Calc: 418.4).

4-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-2-one (13b,yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.87 (d, 1H, 8.1 Hz),7.65-7.71 (m, 4H), 7.19-7.23 (m, 1H), 7.02-7.05 (m, 6H), 4.51 (s, 2H),4.15 (t, 2H, 5.2 Hz), 3.44 (t, 2H, 5.1 Hz); LC/MS: m/z=415.1[M+H]+(Calc: 414.4).

2-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)ethanol (13c,yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.81-8.1 (m, 5H), 7.58-7.64(m, 1H), 7.18-7.24 (m, 6H), 3.76-3.94 (m, 4H); LC/MS: m/z=376.1[M+H]+(Calc: 375.4).

N¹-(4-(4-(4-Fluorophenoxy)phenyl)quinazohn-2-yl)-N²,N²-dimethylethane-1,2-diamine(13d, yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 8.23 (d, 1H, 8.1 Hz),8.12 (dd, 1H, 7.8 & 8.2 Hz), 7.98 (d, 2H, 8.3 Hz), 7.81-7.84 (m, 1H),7.64-7.68 (m, 1H), 7.18-7.25 (m, 6H), 4.21 (t, 2H, 6.1 Hz), 3.54-3.58(m, 2H); LC/MS: m/z=403.1 [M+H]+(Cale: 402.5).

4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-amine (13e, yellow solid): ¹-H-NMR (400 MHz, CD₃OD): δ 7.81-7.81 (m, 1H), 7.61-7.69 (m, 3H), 7.49-7.52(m, 1H), 7.19-7.23 (m, 1H), 7.01-7.05 (m, 6H); LC/MS: m/z=332.0[M+H]+(Calc: 331.3).

(S)-Methyl1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)pyrrolidine-2-earboxylate(13f, white solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.52-7.84 (m, 5H),6.98-7.12 (m, 7H), 4.67-4.71 (m, 1H), 3.82-3.94 (m, 2H), 3.61 (s, 3H),2.28-2.34 (m, 1H), 2.04-2.12 (m, 3H); LC/MS: m/z=444.1 [M+H]+(Calc:443.5).

4-(4-(4-Fluorophenoxy)phenyl)-2-(1-methylhydrazinyl)quinazoline (13 g,yellow solid): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.78-7.83 (m, 3H), 7.71-7.74(m, 1H), 7.58 (d, 1H, 8.3 Hz), 7.21-7.33 (m, 4H), 7.16 (d, 2H, 8.3 Hz),5.07 (s, 2H, —NH2), 3.38 (s, 3H); LC/MS: m/z=361.1 [M+H]+(Calc: 360.4).

2-(4-Ethylpiperazin-1-yl)-4-(4-(4-fluorophenoxy)phenyl)quinazoline (13h, yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.88 (d, 1H, 8.1 Hz), 7.76(d, 2H, 8.8 Hz), 7.66-7.68 (m, 2H), 7.17-7.21 (m, 1H), 7.11-7.15 (m,6H), 4.09-4.15 (m, 4H), 2.55-2.71 (m, 6H), 1.22 (t, 3H, 7.2 Hz); LC/MS:m/z=429.1 [M+H]+ (Calc: 428.5).

1-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)piperidin-4-ol (13i,yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.78 (d, 1H, 8.1 Hz), 7.67 (d,2H, 8.8 Hz), 7.55-7.59 (m, 2H), 7.01-7.11 (m, 6H), 4.56-4.62 (m, 2H),3.89-3.93 (m, 1H), 3.28-3.41 (m, 2H), 1.92-1.98 (m, 214), 1.52-1.58 (m,214); LC/MS: m/z=416.2 [M+H]+(Calc: 415.5).

2-(4-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-1-yl)ethanol(13j, yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H, 8.1 Hz),7.67 (d, 21-1, 8.8 Hz), 7.58-7.61 (m, 2H), 7.10-7.14 (m, 1H), 7.01-7.05(m, 6H), 4.06-4.12 (m, 4H), 3.69-3.73 (m, 2H), 2.66-2.76 (m, 6H); LC/MS:m/z=445.1 [M+H]+(Calc: 444.5).

4-(4-(4-Flu o rop h en oxy)phenyl)-2-(4-methylp iperazin-1-yl)quinazoline (13k, yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ7.89 (d, 1H, 8.3 Hz), 7.76 (d, 2H, 8.8 Hz), 7.66-7.68 (m, 2H), 7.17-7.21(m, 1H), 7.10-7.13 (m, 6H), 4.11-4.16 (m, 4H), 2.63-2.68 (m, 4H), 2.46(s, 31-1); LC/MS: m/z=415.1 [M+H]+(Calc: 414.5).

(S)-1-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)pyrrolidine-2-carboxamide(131, yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.93 (d, 1H, 8.3 Hz),7.76 (d, 211, 8.8 Hz), 7.69-7.71 (m, 2H), 7.21-7.25 (m, 1H), 7.07-7.13(m, 6H), 4.72-4.74 (m, 1H), 3.91-3.96 (m, 1H), 3.81-3.86 (m, 1H),2.31-2.39 (m, 1H), 2.01-2.21 (m, 3H); LC/MS: m/z=429.1 [M+H]+(Calc:428.5).

(2S,4R)-Methyl1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-4-hydroxypyrrolidine-2-carboxylate(13m, yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.84-7.89 (m, 1H),7.62-7.69 (m, 4H), 7.16-7.21 (m, 1H), 7.0-7.06 (m, 6H), 4.79 (dd, 1H,7.6 & 8.0 Hz), 4.54-4.58 (m, 1H), 3.86-3.94 (m, 2H), 3.58-3.64 (m, 3H),2.32-2.38 (m, 1H), 2.11-2.19 (m, 1H); LC/MS: m/z=460.1 [M+H]+(Calc:459.5).

4-(4-(4-Fluorophenoxy)phenyl)-N-methylquinazolin-2-amine (13n, yellowsolid): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.6-7.7 (m, 4H), 7.49 (d, 1H, 8.5Hz), 7.21-7.29 (m, 3H), 7.12-7.16 (m, 3H), 7.08 (d, 2H, 8.7 Hz), 2.85(d, 3H, 4.8 Hz); LC/MS: m/z=346.1 [M+H]+(Calc: 345.4).

N-(3-(1H-imidazol-1-yl)propyl)-4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-amine(13o, yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.77 (d, 1H, 8.3 Hz),7.69 (s, 1H), 7.6-7.64 (m, 3H), 7.56 (d, 1H, 8.1 Hz), 7.11-7.16 (m, 1H),7.0-7.12 (m, 7H), 6.97 (s, 1H), 4.09 (t, 2H, 7.011z), 3.51 (t, 2H, 6.8Hz), 2.1-2.16 (m, 2H); LC/MS: m/z=440.2 [M+H]+(Calc: 439.5).

N¹-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)-N³,N³-dimethylpropane-1,3-diamine(13p, yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.85 (d, 1H, 8.1 Hz),7.66-7.73 (m, 4H), 7.18-7.22 (m, 1H), 6.98-7.14 (m, 6H), 5.75 (br, 1H),3.68-3.74 (m, 2H), 2.74-2.8 (m, 2H), 2.51 (s, 6H), 2.04-2.09 (m, 2H);LC/MS: m/z=417.1 [M+H]+(Cale: 416.5).

(R)-3-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol(13q, yellow oil): ¹H-NMR (400 MHz, CDCl₃): δ 7.89 (d, 1H, 8.1 Hz),7.66-7.74 (m, 4H), 7.24-7.27 (m, 1H), 7.09-7.14 (m, 6H), 5.75 (br, 1H),3.89-3.94 (m, 1H), 3.63-3.77 (m, 4H); LC/MS: m/z=406.1 [M+H]+(Cale:405.4).

(S)-3-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol(13r, yellow solid): ¹H-NMR (400 MHz, CDCl₃) δ: 7.89 (d, 1H, 8.1 Hz),7.68-7.75 (m, 4H), 7.28-7.3 (m, 1H), 7.09-7.14 (m, 6H), 5.75 (br, 1H),3.89-3.94 (m, 1H), 3.63-3.77 (m, 4H), 2.11 (br, 2H, —OH); LC/MS:m/z=406.1 [M+H]+(Cale: 405.4).

(S)-2-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)succinamide(13s, white solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.94-7.98 (m, 1H),7.74-7.79 (m, 3H), 7.66 (d, 1H, 8.5 Hz), 7.32-7.36 (m, 1H), 7.09-7.14(m, 6H), 5.14-5.17 (m, 1H), 2.81-2.92 (m, 2H); LC/MS: m/z=446.2[M+H]+(Calc: 445.4).

4-(4-(4-Fluorophenoxy)phenyl)-N-01R,3S,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)quinazolin-2-amine(13t, yellow solid): ¹H-NMR (400 MHz, CDCl₃): δ 7.85 (d, 1H, 8.1 Hz),7.67-7.74 (m, 4H), 7.17-7.21 (m, 1H), 7.09-7.14 (m, 6H), 5.16-5.18 (m,1H), 4.65-4.67 (m, 1H), 3.28-3.25 (m, 2H), 2.67-2.82 (5H), 2.11-2.19 (m,3H), 1.5-1.67 (m, 3H), 1.25-1.3 (m, 1H); LC/MS: m/z=469.1 [M+H]+(Calc:468.6).

2-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,3-diol(13u, yellow solid): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.61-7.66 (m, 4H), 7.4(d, 1H, 8.3 Hz), 7.21-7.26 (m, 2H), 7.07-7.16 (m, 5H), 6.73-6.78 (m, 1H,NH), 4.57-4.62 (m, 2H, —OH), 4.02-4.07 (m, 1H), 3.49-3.53 (m, 4H);LC/MS: m/z=406.1 [M+H]+(Calc: 405.4).

1-(2-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)ethyl)-imidazolidin-2-one(13v, yellow solid): ¹H-NMR (400 MHz, CD₃OD): δ 7.87 (d, 1H, 8.6 Hz),7.61-7.72 (m, 4H), 7.09-7.14 (m, 6H), 3.73 (dd, 2H, 5.9 & 6.3 Hz), 3.6(dd, 2H, 6.3 & 7.6 Hz), 3.48 (dd, 2H, 5.9 & 6.3 Hz), 3.35 (dd, 2H, 6.3 &7.6 Hz);

LC/MS: m/z=444.1 [M+H]+(Calc: 443.5).

2-(1-(4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)hydrazinyl)ethanol(13w, yellow solid): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.71-7.76 (m, 3H),7.64-7.68 (m, 1H), 7.53 (d, 1H, 8.3 Hz), 7.21-7.26 (m, 2H), 7.14-7.18(m, 3H), 7.09 (d, 2H, 8.8 Hz), 4.98 (br, 2H, —NH₂), 4.58 (br, 1H, —OH),3.85 (t, 2H, 7.3 Hz), 3.6-3.64 (m, 2H); LC/MS: m/z=391.1 [M+H]+(Calc:390.4).

2-((4-(4-(4-Fluorophenoxy)phenyl)quinazolin-2-yl)amino)acetamide (13×,white solid): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.81 (d, 1H, 8.1 Hz),7.7-7.76 (m, 3H), 7.55 (d, 1H, 8.6 Hz), 7.35-7.38 (m, 2H, —CONH₂),7.15-7.31 (m, 7H), 7.03 (br, 1H, NH), 3.96 (d, 2H, 6.1 Hz); LC/MS:m/z=389.2 [M+H]+(Calc: 388.4).

2-Ethoxy-4-(4-(4-fluorophenoxy)phenyl)quinazoline (13y, white solid):¹H-NMR (400 MHz, CDCl₃): δ 7.97 (ddd, 1H, 0.6, 1.3 & 8.6 Hz), 7.78-7.81(m, 1H), 7.69-7.74 (m, 3H), 7.32 (dt, 1H, 1.3 & 8.3 Hz), 6.99-7.04 (m,6H), 4.53 (q, 2H, 7.2 Hz), 1.43 (t, 3H, 7.1 Hz); LC/MS: m/z=361.1[M+11]+ (Calc: 360.4).

4-(4-(4-Florophenoxy)phenyl)-2-(pyridin-2-yloxy)quinazoline (13z, whitesolid): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.3 (d, 1H, 8.3 Hz), 8.14-8.17 (m,2H), 7.85-7.96 (m, 4H), 7.57-7.62 (m, 1H), 7.2-7.34 (m, 6H), 6.54 (d,1H, 8.9 Hz), 6.37 (dd, 1H, 1.3 & 6.9 Hz); LC/MS: m/z=410.0 [M+H]+(Calc:409.4).

Example 4

Representative compounds of the invention have been tested in theFLIPR^(TETRA)® or FLIPR® sodium dye assay with KCl assay andelectrophysiology (EP) assay for sodium channel blocking activity, whichare described in detail above. Representative values are presented inTABLE 2.

TABLE 2 Evaluation of the tested compounds as sodium channel (Na_(v))blockers FLIPR Na_(v)1.7 IC₅₀ EP EP (μM) ± Na_(v)1.7 Na_(v)1.7 COMPOUNDSEM K_(j) (μM) K_(r) (μM) N¹-(4-(4-(4- 0.317 ±fluorophenoxy)phenyl)quinazolin-2-yl)- 0.026N²,N²-dimethylethane-1,2-diamine (13d) 2-((4-(4-(4- 0.369 ±fluorophenoxy)phenyl)quinazolin-2- 0.046 yl)amino)ethanol (13c)(S)-2-{4-[4-(4- 0.836 ± 0.74 ± fluorophenoxy)phenyl]quinazolin-2- 0.0980.05 ylamino}-3-hydroxy-propionamide (13a)4-(4-(4-(4-fluorophenoxy)phenyl)quinazolin- 0.839 ± 2-yl)piperazin-2-one(13b) 0.066 4-(4-(4-fluorophenoxy)phenyl)quinazolin-2- 0.426 ± amine(13e) 0.125 (S)-methyl 1-(4-(4-(4- 0.642 ± 0.62 ± 23.90 ±fluorophenoxy)phenyl)-quinazolin-2- 0.114 0.19 4.71yl)pyrrolidine-2-carboxylate (13f) 4-(4-(4-fluorophenoxy)phenyl)-2-(1-0.309 ± methylhydrazinyl)quinazoline (13g) 0.0412-(4-ethylpiperazin-1-yl)-4-(4-(4- 0.236 ±fluorophenoxy)phenyl)quinazoline (13h) 0.0411-(4-(4-(4-fluorophenoxy)phenyl)quinazolin- 0.428 ± 2-yl)piperidin-4-ol(13i) 0.073 2-(4-(4-(4-(4- 0.104 ± fluorophenoxy)phenyl)quinazolin-2-0.010 yl)piperazin-1-yl)ethanol (13j)4-(4-(4-fluorophenoxy)phenyl)-2-(4- 0.418 ± 0.07 ± 2.09 ±methylpiperazin-1-yl)quinazoline (13k) 0.058 0.02 0.24 (S)-1-(4-(4-(4-0.105 ± 0.19 ± fluorophenoxy)phenyl)quinazolin-2- 0.011 0.07yl)pyrrolidine-2-carboxamide (13l) (2S,4R)-methyl 1-(4-(4-(4- 0.833 ±fluorophenoxy)phenyl)quinazolin-2-yl)-4- 0.162hydroxypyrrolidine-2-carboxylate (13m)N-(3-(1H-imidazol-1-yl)propyl)-4-(4-(4- 0.325 ±fluorophenoxy)phenyl)quinazolin-2-amine 0.084 (13o) N¹-(4-(4-(4- 0.205 ±fluorophenoxy)phenyl)quinazolin-2-yl)- 0.020N³,N³-dimethylpropane-1,3-diamine (13p) 4-(4-(4-fluorophenoxy)phenyl)-N-0.294 ± methylquinazolin-2-amine (13n) 0.048 (R)-3-((4-(4-(4- 0.071 ±0.22 ± fluorophenoxy)phenyl)quinazolin-2- 0.011 0.03yl)amino)propane-1,2-diol (13q) (S)-3-((4-(4-(4- 0.320 ±fluorophenoxy)phenyl)quinazolin-2- 0.079 yl)amino)propane-1,2-diol (13r)(S)-2-((4-(4-(4- 0.313 ± fluorophenoxy)phenyl)quinazolin-2- 0.054yl)amino)succinamide (13s) 4-(4-(4-fluorophenoxy)phenyl)-N- 0.228 ± 0.02± ((1R,3S,5S)-9-methyl-9- 0.053 0.00 azabicyclo[3.3.1]nonan-3-yl)quinazolin-2-amine (13t) 2-((4-(4-(4- 0.208 ± 0.64 ± 55.33 ±fluorophenoxy)phenyl)quinazolin-2- 0.111 0.02 14.77yl)amino)propane-1,3-diol (13u) 1-(2-((4-(4-(4- 0.204 ± 0.46 ± 23.67 ±fluorophenoxy)phenyl)quinazolin-2- 0.071 0.04 2.91yl)amino)ethyl)imidazolidin-2-one (13v) 2-(1-(4-(4-(4- 0.070 ±fluorophenoxy)phenyl)quinazolin-2- 0.017 yl)hydrazinyl)ethanol (13w)2-((4-(4-(4- >20 fluorophenoxy)phenyl)quinazolin-2- yl)amino)acetamide(13x) 4-(4-phenoxyphenyl)quinazoline-2- 0.097 ± 0.12 ± carboxamide (5)0.024 0.01 ethyl 4-(4-phenoxyphenyl)quinazoline-2- 1.570 ± carboxylate(3) 0.456 4-(4-phenoxyphenyl)quinazoline-2- >20 carboxylic acid (4)(S)-1-(4-(4-(4- 0.849 ± fluorophenoxy)phenyl)quinazolin-2- 0.193yl)ethane-1,2-diol (10) 2-ethoxy-4-(4-(4-fluorophenoxy)phenyl)- 0.995 ±quinazoline (13y) 0.164 4-(4-(4-fluorophenoxy)phenyl)-2- 1.910 ±(pyridin-2-yloxy)quinazoline (13z) 0.431

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹, R², R³, and R⁴ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy,hydroxyalkyl, haloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylcarbonylamino, alkylcarbonyloxy, carboxy, alkoxycarbonyl,aminosulfonyl, alkyl sulfonyl amino, (alkylsulfonylamino)alkyl, ureido,(aminocarbonyl)alkylamino, and (carboxyalkyl)amino; G is G¹, G², G³, orG⁴, wherein G¹ is —NR⁵R⁶, wherein R⁵ is H, alkyl, or NH₂, R⁶ is a) H, b)alkyl, c) hydroxyalkyl, d) (aminocarbonyl)alkyl, e)(aminocarbonyl)(hydroxy)alkyl; f) aminoalkyl, g) alkylaminoalkyl, h)dialkylaminoalkyl, i) cycloalkyl, unsubstituted or substituted with oneor more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano; j) (cycloalkyl)alkyl,wherein the cycloalkyl is unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano; k) aryl, unsubstituted or substituted withone or more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano; l) arylalkyl, whereinthe aryl group is unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano; m) heteroaryl, unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano; n)heteroarylalkyl, wherein the heteroaryl group is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano; o)heterocyclo, unsubstituted or substituted with one or more substituentseach independently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano; or p) heterocycloalkyl, wherein theheterocyclo is unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano; or R⁵ and R⁶ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring having carbon atoms and 1 or 2 nitrogen atoms, whereinthe heterocyclic ring is unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofoxo, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;

G² is p is 0, 1 or 2; R⁷ is a) —(CF₁₂)_(q)OH, wherein q is 0, 1, 2, 3,4, or 5; or b) selected from the group consisting of hydrogen, amino,alkylamino, dialkylamino, and alkoxy; and R⁸ is hydrogen or a bond; G³is a 5- or 6-membered heteroaryl containing at least one nitrogen atom,wherein the heteroaryl is unsubstituted or substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl,carboxy, alkoxycarbonyl, and cyano; and G⁴ is —OR⁹, wherein R⁹ is alkyl,alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonylalkyl, carboxyalkyl,alkoxycarbonylalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl,wherein said aryl and heteroaryl are unsubstituted or substituted withone or more substituents selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano; A is

wherein A¹ is aryl or heteroaryl, any of which is optionallysubstituted; X is —O—, —S—, —SO—, —SO₂—, —CH₂—, or —NH—; and R¹³ and R¹⁴are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl; with the proviso that when G is G¹, where R⁵ is hydrogenor alkyl and R⁶ is hydrogen, alkyl or cycloalkyl, and X is —O—, then notwo of R¹, R², R³ and R⁴ are alkoxy at the same time.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein A is A′ having the structure:

wherein X is —O—, —S—, —SO—, —SO₂—, —CH₂—, or —NH—, and R¹³, R¹⁴, R¹⁵,and R¹⁶ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl.
 3. The compound of claim 1, wherein X is —O—. 4-8.(canceled)
 9. The compound of claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein A is A″ having the structure:

wherein R¹³, R¹⁴, R¹⁵, and R¹⁶ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.
 10. The compound ofclaim 1, wherein A is A″, and R¹, R², R³ and R⁴ are each hydrogen,having the Formula II:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein G is as defined in claim 1, and R¹³, R¹⁴, R¹⁵ and R¹⁶ are areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl.
 11. (canceled)
 12. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein Gis G¹.
 13. The compound of claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein R⁵ in G¹ is H and R⁶ is asdefined in claim
 1. 14. The compound of claim 1, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, wherein R⁵ in G¹ is alkyland R⁶ is as defined in claim
 1. 15. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁵in G¹ is NH₂ and R⁶ is as defined in claim
 1. 16. The compound of claim1, or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R⁶ in G¹ is hydrogen and R⁵ is as defined in claim
 1. 17.(canceled)
 18. The compound of claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein R⁶ in G¹ is alkyl and R⁵ is asdefined in claim
 1. 19. (canceled)
 20. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁶in G¹ is hydroxyalkyl and R⁵ is as defined in claim
 1. 21-22. (canceled)23. The compound of claim 1, or a pharmaceutically acceptable salt,prodrug or solvate thereof, wherein R⁶ in G¹ is (aminocarbonyl)alkyl andR⁵ is as defined in claim
 1. 24. (canceled)
 25. The compound of claim 1,or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R⁶ in G¹ is (aminocarbonyl)(hydroxy)alkyl and R⁵ is as definedin claim
 1. 26. (canceled)
 27. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁶in G¹ is aminoalkyl and R⁵ is as defined in claim
 1. 28. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein R⁶ in G¹ is alkylaminoalkyl and R⁵ is as defined inclaim
 1. 29. The compound of claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein R⁶ in G¹ is dialkylaminoalkyland R⁵ is as defined in claim
 1. 30. (canceled)
 31. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein R⁶ is cycloalkyl, unsubstituted or substituted with oneor more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano, and R⁵ is as definedin claim
 1. 32. The compound of claim 1, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, wherein R⁶ is(cycloalkyl)alkyl, wherein the cycloalkyl is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano,and R⁵ is as defined in claim
 1. 33. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁶is aryl, unsubstituted or substituted with one or more substituents eachindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano, and R⁵ is as defined in claim
 1. 34. Thecompound of claim 1, or a pharmaceutically acceptable salt, prodrug orsolvate thereof, wherein R⁶ is arylalkyl, wherein the aryl group isunsubstituted or substituted with one or more substituents eachindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano, and R⁵ is as defined in claim
 1. 35. Thecompound of claim 1, or a pharmaceutically acceptable salt, prodrug orsolvate thereof, wherein R⁶ is heteroaryl, unsubstituted or substitutedwith one or more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonyl, carboxy, alkoxycarbonyl, and cyano, and R⁵ is as definedin claim
 1. 36. The compound of claim 1, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, wherein R⁶ isheteroarylalkyl, wherein the heteroaryl group is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano,and R⁵ is as defined in claim
 1. 37-38. (canceled)
 39. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein R⁶ is heterocyclo, unsubstituted or substituted withone or more substituents each independently selected from the groupconsisting of oxo, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano,and R⁵ is as defined in claim
 1. 40. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein G¹is selected from the group consisting of

wherein R¹⁷ is hydrogen or C₁₋₄ alkyl.
 41. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁶is heterocycloalkyl, wherein the heterocyclo group is unsubstituted orsubstituted with one or more substituents each independently selectedfrom the group consisting of oxo, alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano,and R⁵ is as defined in claim
 1. 42. (canceled)
 43. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 5- or 6-membered heterocyclic ring having carbonatoms and 1 or 2 nitrogen atoms, wherein the heterocyclic ring isunsubstituted or substituted with one or more substituents eachindependently selected from the group consisting of oxo, alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano. 44-51. (canceled)
 52. The compound of claim1, or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein G is G²

wherein p is 0, 1 or 2; R⁷ is a) —(CH₂)_(q)OH, wherein q is 0, 1, 2, 3,4 or 5; or b) selected from the group consisting of hydrogen, amino,alkylamino, dialkylamino, and alkoxy; and R⁸ is hydrogen or a bond. 53.The compound of claim 52 or a pharmaceutically acceptable salt, prodrugor solvate thereof, wherein p is
 0. 54. The compound of claim 52 or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein pis
 1. 55. The compound of claim 52, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein R⁸ is hydrogen.
 56. Thecompound of claim 52, or a pharmaceutically acceptable salt, prodrug orsolvate thereof, wherein R⁸ is a bond.
 57. The compound of claim 52, ora pharmaceutically acceptable salt, prodrug or solvate thereof, whereinR⁷ is hydrogen, amino or alkoxy.
 58. (canceled)
 59. The compound ofclaim 52, or a pharmaceutically acceptable salt, prodrug or solvatethereof, wherein R⁷ is —(CH₂)_(q)OH and q is 0, 1, 2, or
 3. 60-61.(canceled)
 62. The compound of claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof, wherein G is G³, which is a 5- or6-membered heteroaryl containing at least one nitrogen atom, wherein theheteroaryl is unsubstituted or substituted with one or more substituentseach independently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano.
 63. The compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein G⁴is —OR⁹, wherein R⁹ is alkyl, aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,amiroalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano.
 64. The compound of claim 63, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁹is alkyl which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano.
 65. The compound of claim 63, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁹is heteroaryl which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano.
 66. The compound of claim 63, or apharmaceutically acceptable salt, prodrug or solvate thereof, wherein R⁹is aryl which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy,alkoxycarbonyl, and cyano. 67-68. (canceled)
 69. The compound of claim1, having the Formula III:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.
 70. The compound ofclaim 1, having the Formula IV;

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.
 71. The compound ofclaim 1, having the Formula V:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl. 72-73. (canceled) 74.The compound of claim 1, wherein said compound isN¹-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-N²,N²-dimethylethane-1,2-diamine;2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)ethanol;(S)-2-{4-[4-(4-fluorophenoxy)phenyl]quinazolin-2-ylamino}-3-hydroxy-propionamide;4-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-2-one;4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-amine; (S)-methyl1-(4-(4-(4-fluorophenoxy)phenyl)-quinazolin-2-yl)-pyrrolidine-2-carboxylate;4-(4-(4-fluorophenoxy)phenyl)-2-(1-methylhydrazinyl)quinazoline;2-(4-ethylpiperazii-1-yl)-4-(4-(4-fluorophenoxy)phenyl)quinazoline;1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yepiperidin-4-ol;2-(4-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)piperazin-1-yl)ethanol;4-(4-(4-fluorophenoxy)phenyl)-2-(4-methylpiperazin-1-yl)quinazoline;(S)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)pyrrolidine-2-carboxamide;4R)-methyl1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-4-hydroxy-pyrrolidine-2-carboxylate;N-(3-(1H-imidazol-1-yl)propyl)-4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-amine;N¹-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)-N³,N³-dimethylpropane-1,3-diamine;4-(4-(4-fluorophenoxy)phenyl)-N-methylquinazolin-2-amine;(R)-3(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol;(S)-3-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,2-diol;(S)-2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)succinamide;4-(4-(4-fluorophenoxy)phenyl)-N-((1R,3S,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)quinazolin-2-amine;2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)propane-1,3-diol;1-(2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yeamino)ethyl)imidazolidin-2-one;2-(1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)hydrazinyeethanol;2-((4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)amino)acetamide;4-(4-phenoxyphenyl)quinazoline-2-carboxamide; ethyl4-(4-phenoxyphenyl)quinazoline-2-carboxylate;4-(4-phenoxyphenyl)quinazoline-2-carboxylic acid;(5)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)ethane-1,2-diol;2-ethoxy-4-(4-(4-fluorophenoxy)phenyl)-quinazoline;4-(4-(4-fluorophenoxy)phenyl)-2-(pyridin-2-yloxy)quinazoline; or apharmaceutically acceptable salt, prodrug or solvate thereof.
 75. Apharmaceutical composition, comprising the compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, and apharmaceutically acceptable carrier.
 76. A method of treating a disorderresponsive to the blockade of sodium channels in a mammal suffering fromsaid disorder, comprising administering to a mammal in need of suchtreatment an effective amount of a compound as claimed in claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof.
 77. Themethod of claim 76, wherein a disorder responsive to the blockade ofTTX-resistant sodium channels is treated.
 78. The method of claim 76,wherein a disorder responsive to the blockade of TTX-sensitive sodiumchannels is treated.
 79. The method of claim 76, wherein a disorderresponsive to the blockade of Na_(v)1.7 sodium channels is treated. 80.A method for treating stroke, neuronal damage resulting from headtrauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, pain, migraine, familial primary erythromelalgia,paroxymal extreme pain disorder, cerebellar atrophy, ataxia, dystonia,tremor, mental retardation, autism, a neurodegenerative disorder, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia in a mammal, comprisingadministering an effective amount of a compound as claimed in claim 1,or a pharmaceutically acceptable salt, prodrug or solvate thereof, to amammal in need of such treatment.
 81. The method of claim 80, whereinthe method is for treating pain.
 82. The method of claim 81, wherein themethod is for preemptive or palliative treatment of pain.
 83. The methodof claim 81, wherein said pain is selected from the group consisting ofchronic pain, inflammatory pain, neuropathic pain, postsurgical pain,acute pain, and surgical pain.
 84. A method of modulating sodiumchannels in a mammal, comprising administering to the mammal at leastone compound as claimed in claim 1, or a pharmaceutically acceptablesalt, prodrug or solvate thereof.
 85. The method of claim 84, whereinthe Na_(v)1.7 sodium channel is modulated.
 86. A compound having theFormula I as claimed in claim 1, wherein the compound is ³H, ¹¹C, or ¹⁴Cradiolabeled, or a pharmaceutically acceptable salt, prodrug or solvatethereof.
 87. A method of screening a candidate compound for the abilityto bind to a binding site on a protein using a radiolabeled compound ofclaim 86, comprising i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit offragment, respectively, to form a conjugate ii) titrating the mixturewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment. 88-92. (canceled)
 93. A method ofpreparing a pharmaceutical composition, comprising admixing atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, with apharmaceutically acceptable carrier.